The critical role of commensal microbiota in regulating the host immune response has been established. In addition, it is known that host–microbial interactions are bidirectional, and this interplay is tightly regulated to prevent chronic inflammatory disease. Although many studies have focused on the role of classic T cell subsets, unconventional lymphocytes such as NKT cells and innate lymphoid cells also contribute to the regulation of homeostasis at mucosal surfaces and influence the composition of the intestinal microbiota. In this review, we discuss the mechanisms involved in the cross-regulation between NKT cells, innate lymphoid cells, and the gut microbiota. Moreover, we highlight how disruptions in homeostasis can lead to immune-mediated disorders.

Intestinal homeostasis is dependent on the bidirectional dialogue between the host intestinal immune cells and commensal bacteria (1). Typically, there is a symbiotic relationship between the intestinal cells and the microbiota. However, the intestinal microbiota is highly varied between individuals, and dysregulation of commensals can have pathological consequences, such as inflammatory bowel disease (IBD). Many studies have focused on the role of Th17, regulatory T cells (Tregs), and classic T cell subsets in intestinal immunity. NKT cells and innate lymphoid cells (ILCs) have been implicated in the regulation of mucosal immunity, but their roles are less well understood, and thus this review focuses on their roles in intestinal immunity.

NKT cells are a distinct population of T lymphocytes that display features characteristic of NK cells and conventional T cells (24). NKT cells are CD1d restricted and can be broadly delineated into two subtypes. Type I invariant NKT (iNKT) cells express an invariant TCR α-chain encoded by Vα14Jα18 in mice and Vα24Jα18 in humans, and a limited number of TCR β-chains. Type I iNKT cells are activated by the lipid α‐galactosylceramide (α-GalCer). In contrast, type II NKT cells, which express diverse αβ TCRs, recognize different lipid Ags (5) and are not activated by α-GalCer (Table I). Type I iNKT cells have been studied extensively and can be further divided into subsets similar to CD4 T helper subsets, namely NKT1 cells are T-bet+ and produce high levels of IFN-γ, NKT2 cells are PLZFhigh and produce IL-4 and IL-13, and NKT17 cells are retinoic acid-related orphan receptor (ROR)γt+ and secrete Th17-type cytokines (6, 7). NKT1 cells represent most type I NKT cells in liver and spleen in C57BL/6 mice and primarily express NK1.1 and IL-12R. NKT2 cells are the most enriched type I NKT cell subset in BALB/c mice, and they are the primary subset present in the lungs and intestines of C57BL/6 mice. NKT17 cells are mainly present in the lung, skin, and lymph nodes. Although iNKT cells express a semi-invariant TCR α-chain, they recognize a diverse array of lipid Ags. Additionally, most studies that focus on α-GalCer–reactive NKT cells are describing iNKT cells; however, α-GalCer–reactive, CD1d-restricted NKT cells that use different TCR α-chains have been identified in mice (8) and humans (911).

Table I.

Mouse and human NKT cells

MouseHuman
Type I   
 TCR Vα14Jα18, Vβ8.2,7,2 Vα24-Jα18, Vβ11 
 Subsets NKT1, NKT2, NKT17, NKTFH, NKT10 NKT1, NKT2, NKT17, NKTFH 
 Reactivity α-GalCer α-GalCer 
 NK receptors NK1.1+/− CD161+/− 
 Coreceptor CD4, DN CD4, CD8, DN 
Type II   
 TCR Diverse Diverse 
 Subsets CD4, DN CD4, CD8 
 Reactivity Sulfatide Sulfatide 
 NK receptors NK1.1+/− CD161+/− 
MouseHuman
Type I   
 TCR Vα14Jα18, Vβ8.2,7,2 Vα24-Jα18, Vβ11 
 Subsets NKT1, NKT2, NKT17, NKTFH, NKT10 NKT1, NKT2, NKT17, NKTFH 
 Reactivity α-GalCer α-GalCer 
 NK receptors NK1.1+/− CD161+/− 
 Coreceptor CD4, DN CD4, CD8, DN 
Type II   
 TCR Diverse Diverse 
 Subsets CD4, DN CD4, CD8 
 Reactivity Sulfatide Sulfatide 
 NK receptors NK1.1+/− CD161+/− 

DN, double negative.

In contrast to classic T cell subsets, iNKT cells establish long-term residency within the tissues and do not circulate (1214). In mice, most iNKT cells express CD4+ or are CD4CD8 double negative (15), and in humans iNKT cells express CD4+, CD8+, or are double negative (1619). In addition, NKT cells are phenotypically similar to effector T cells due to their expression of non-lymphoid tissue homing chemokine receptors such as CCR2, CCR5, and CXCR3. Additional subsets of iNKT cells have been identified following their activation in vivo. Specifically, there is a small population that, similar to follicular helper T cells, secrete IL-21, support germinal center development, and express Bcl-6, referred to as iNKTFH cells (2022). In addition, most iNKT cell subsets express PLZF; however, there is a regulatory iNKT cell population, NKT10 cells, that expresses E4BP4 (23, 24).

NKT cells can be activated through TCR-dependent and independent mechanisms, in response to self and foreign Ags (25, 26). In fact, CD1d molecules present Ags derived from allergens, bacteria, and fungi to iNKT cells. In addition, danger signals such as those induced by TLR signaling can lead to the induction of CD1d-mediated NKT cell responses to self-antigens. Moreover, cytokines such as IL-12 and IL-18 can drive NKT cell activation. Following activation, NKT cells rapidly produce Th1-, Th2-, and Th17-type cytokines (27, 28), and they have been shown to play a critical role in the regulation of intestinal immunity (2931).

iNKT cells are located within the intestines in the absence of microbiota (3234). There are differences in mucosal NKT cell subpopulations in mice and humans. Whereas iNKT cells are present at high frequencies in the fetal intestine in humans, this population is absent at birth in mice (32, 35, 36). However, the population of murine intestinal iNKT cells increases during the first few weeks of age (35, 36). CD1d is expressed by numerous cells within the intestines, including intestinal epithelial cells, ILCs, B cells, dendritic cells (DCs), and macrophages, and CD1d expression has been shown to be a key regulator of intestinal inflammation.

A recent study demonstrated a critical role for vitamin A in regulating the mucosal iNKT cell population in mice (37). Vitamin A served as a negative regulator by inducing the P2X7 receptor, resulting in the death of tissue-resident NKT cells, which was important for intestinal homeostasis. Moreover, crosstalk between the NKT/CD1d axis and the colonization of commensal bacteria is evident, as Nieuwenhuis et al. (38) found that CD1d-deficient mice had an increased bacterial burden following exposure to Pseudomonas aeruginosa. It was shown that CD1d is required for intestinal colonization of both Gram-positive and Gram-negative commensals. To further establish a role for CD1d-dependent NKT cells, mice were injected with α-GalCer and Paneth cells degranulated in WT mice, but not in CD1d-deficient animals (38). Interestingly, in the absence of CD1d, there was a defect in the morphology and function of granules containing antimicrobial peptides.

Cell membranes are largely composed of phospholipids, and many of these ubiquitously expressed lipids have been reported to be CD1d-restricted Ags (39). Both type I and type II murine NKT cell hybridomas recognize phosphatidylinositol, phosphatidylethanolamine, and phosphatidylglycerol (40). Mammalian phospholipids differ from their microbial counterparts in the fatty acyl chain composition or the position of the fatty acyl molecules at the sn-1 and sn-2 positions of the glycerol backbone, which can affect iNKT cell responses (39).

As mentioned above, the first α-GalCer Ag shown to activate iNKT cells was isolated from a marine sponge, Agelas mauritianus (41). Then, a gut commensal, Bacteroides fragilis, was shown to contain an α-GalCer, namely α-GalCerBf (42), that activates both human and mouse iNKT cells. Following these studies, Bacteroides vulgatus and Prevotella copri were demonstrated to produce α-GalCer (43). In later studies, this same group performed a screen to identify additional Ags by examining the intestinal tracts of mice (44). They observed 1–15 pmol of α-GalCer per milligram of protein in the cecum and the colon, which was absent in germ-free mice. In addition, they found that diet, inflammation, and infection could negatively impact α-GalCer levels (44).

Commensal bacteria have been shown to regulate NKT cell homeostasis. Elegant studies by Olszak et al. (32) examining iNKT cells in germ-free mice showed that these cells were significantly elevated in the colonic lamina propria and lungs, compared with specific pathogen-free mice. The increase in iNKT cells was correlated with higher levels of IL-1β and IL-13 and with increased susceptibility to oxazolone-induced colitis and OVA-induced allergic lung inflammation. Importantly, restoration of NKT cell homeostasis was age/time-dependent, as colonization of neonatal mice with conventional microbiota was protective against mucosal iNKT accumulation and related pathology. However, colonization of adult germ-free mice did not protect against colitis-induced mortality and lung inflammation. These data suggest that microbial regulation of intestinal iNKT cells occurs early and persists. In addition, the homing of iNKT cells to the mucosa was found to be CXCL16-dependent. In contrast, studies by An et al. (36) found that monocolonization of germ-free mice with WT B. fragilis, but not a mutant strain deficient in serine palmitoyltransferase, restored mucosal iNKT cell levels without inducing CXCL16. These data and others indicate that there are multiple levels of regulation, as studies by Wieland Brown et al. (42) demonstrated that microbial-derived CD1d-binding lipids from the same organism vary in their ability to induce NKT cell activation and proliferation. In contrast to iNKT cells, the regulation of type II NKT cells by commensal microbiota is poorly understood.

NKT cell Ags are present in the bacteria found within the intestinal microbiota, and several CD1d-restricted mucosal Ags have been identified. These include glycosphingolipids from Sphingomonas spp., glycolipid Ags from Borrelia burgdorferi, and diacylglycerols from various pathogenic bacteria (4548). There are differences in mouse and human iNKT cell responses to α-galactosyl diacylglycerolipid Ags derived from B. burgdorferi (46). Mouse iNKT cells are best activated by BbGL-2c, whereas human iNKT cells are more responsive to Ags with a high number of unsaturated fatty acids, such as BbGL-2f (46). Streptococcus pneumoniae expresses an α-linked diacylglycerol that can activate both mouse and human iNKT cells (49). Lipid extracts from Helicobacter pylori have been reported to induce iNKT cell proliferation (50). In addition to bacterial Ags, a CD1d-specific Ag has been identified for Candida albicans (51). Another fungal glycosphingolipid Ag, asperamide B, has been shown to activate both mouse and human iNKT cells in a CD1d-dependent, MyD88-independent manner (52).

NKT cells play an integral role in intestinal inflammation. IBDs, such as Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by aberrant inflammation within the gastrointestinal (GI) tract (53). In an oxazolone colitis model, which is a murine model of UC, NKT cells were found to induce disease through their production of IL-13, as disease could not be induced in NKT cell–deficient animals (54). In contrast, in a dextran sulfate sodium–induced colitis model, IL-9–producing iNKT cells were found to be protective due to their suppression of IFN-γ and IL-17A production. Collectively, these data suggest that iNKT cells are beneficial in Th1 models, but they can promote disease in Th2 models of intestinal inflammation (30).

In humans, type II NKT cells comprise a large population of cells in the UC lamina propria (55). Fuss et al. (55) stained lamina propria mononuclear cells (LPMCs) with lysosulfatide-loaded tetramer and found that LPMCs from UC patients bind sulfatide glycolipid–loaded CD1d tetramer. Moreover, UC LPMCs produced IL-13 following stimulation by sulfatide glycolipid in a CD1d-dependent manner. To investigate the role of type II NKT cells in colitis, Liao et al. (56) generated a transgenic mouse model that expressed high levels of CD1d and an autoreactive, type II NKT cell TCR (CD1dTg/24αβTg mice). Notably, the double-transgenic CD1dTg/24αβTg mice spontaneously develop IBD, in contrast to single-transgenic CD1dTg or 24αβTg mice. These data suggest that high CD1d expression increased the numbers of type II NKT cells, which drives disease progression. Moreover, the authors found that treatment with broad-spectrum antibiotics ameliorated disease in CD1dTg/24αβTg mice (56). Overall, these studies suggest a pivotal role for the intestinal microbiota in promoting NKT cell–induced inflammation, which is in contrast to the suppressive role that commensals play in regulating iNKT cell expansion.

The link between chronic inflammation in IBD patients and increased risk for colorectal cancer has been well established. As described above, NKT cells can drive intestinal inflammation in IBD, and thus their role in the development of intestinal tumors has been investigated (57, 58). Studies by Cardell and colleagues (57, 58) using two different iNKT cell–deficient mouse strains found that iNKT cells promoted the development of spontaneous intestinal polyps in ApcMin/+ mice, a model for early stage human colorectal cancer. Interestingly, in a human study of colorectal cancer, an increased infiltration of Vα24 NKT cells was found in colorectal carcinoma cases, compared with controls, and NKT cell infiltration in colorectal carcinomas was correlated with better outcomes (59).

ILCs were identified relatively recently as lineage-negative cells that mount rapid responses against pathogens and contribute to the regulation of adaptive immunity (60). Present at relatively low frequencies in peripheral blood, ILCs are primarily tissue resident and enriched at mucosal barrier sites (6163), where they contribute to tissue homeostasis and repair (64). Initially categorized in three groups based on master regulators and effector cytokines (65), ILCs were later reclassified in five distinct populations based on developmental stages, that is, NK cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducers (60) (Table II). ILC1s, ILC2s, and ILC3s are defined helper ILCs because they are regarded as the innate functional equivalent of T helper subsets. ILC1s, similar to Th1 cells, express T-bet, and their responses are elicited by IL-12 in combination with IL-2, IL-18, or IL-15 (6668). The ensuing secretion of IFN-γ and TNF-α enables ILC1s to respond to intracellular pathogens (67, 69, 70). ILC2s, the functional equivalent of Th2 cells, are essential for the control of intestinal parasites, but they also take part in allergic inflammation, particularly in the lung (7176). They express the transcription factor GATA3 and, upon activation by IL-25, IL-33, or stromal lymphopoietin (TSLP), they produce IL-4, IL-5, IL-9, IL-13, and amphiregulin (7378). ILC2s can also produce IL-10 when activated in the presence of specific soluble factors (7982), and they appear to be the main source of IL-10 among helper ILCs in murine intestine (79). A controversy is still ongoing about the existence of IL-10–producing ILCs identified as a separate intestinal subset, the regulatory ILCs (83). ILC3s, similar to Th17 cells, express RORγt and produce IL-17A and IL-22 in response to IL-23 and IL-1β stimulation (8488). They are key for responses to extracellular bacteria and fungi, as well as maintenance of tissue homeostasis (87).

Table II.

Mouse and human ILCs

NKILC1ILC2ILC3LTi
Mouse      
 NK receptorsa NK1.1, NKp46 NK1.1, NKp46 KLRG1 NKp46  
 Other markers CD49b CD49a ST2 CCR6 CD4, CCR6 
 Soluble signals IL-2, IL-18 IL-2, IL-12, IL-18, IL-15 IL-25, IL-33, TSLP IL-1β, IL-23 IL-1β, IL-23 
 Function Cytotoxic, helper Helper Helper Helper Helper 
 Cytokine profile Th1 Th1 Th2 Th17 Th17 
Human      
 NK receptors NKp46 NKp46 NKp30, KLRG1 NKp44, NKp46, NKp30  
 Other markers CD56, CD94 CD56, CD103 CRTH2 CCR6, CD56 CCR6, CD161 
 Soluble signals IL-2, IL-18 IL-2, IL-12, IL-18 IL-25, IL-33, TSLP IL-1β, IL-23 IL-1β, IL-23 
 Function Cytotoxic Helper Helper Helper Helper 
 Cytokine profile Th1 Th1 Th2 Th17 Th17 
NKILC1ILC2ILC3LTi
Mouse      
 NK receptorsa NK1.1, NKp46 NK1.1, NKp46 KLRG1 NKp46  
 Other markers CD49b CD49a ST2 CCR6 CD4, CCR6 
 Soluble signals IL-2, IL-18 IL-2, IL-12, IL-18, IL-15 IL-25, IL-33, TSLP IL-1β, IL-23 IL-1β, IL-23 
 Function Cytotoxic, helper Helper Helper Helper Helper 
 Cytokine profile Th1 Th1 Th2 Th17 Th17 
Human      
 NK receptors NKp46 NKp46 NKp30, KLRG1 NKp44, NKp46, NKp30  
 Other markers CD56, CD94 CD56, CD103 CRTH2 CCR6, CD56 CCR6, CD161 
 Soluble signals IL-2, IL-18 IL-2, IL-12, IL-18 IL-25, IL-33, TSLP IL-1β, IL-23 IL-1β, IL-23 
 Function Cytotoxic Helper Helper Helper Helper 
 Cytokine profile Th1 Th1 Th2 Th17 Th17 
a

Expression of NK receptors and most other markers is limited to subsets of each helper ILC population.

LTi, lymphoid tissue inducer.

In the GI tract, each helper ILC subset has a specific distribution, with differences between species (61, 63, 89, 90). In humans, lamina propria CD127+ ILC1s are most abundant in the duodenum and tend to decrease going toward the colon, whereas ILC3s increase in numbers from the upper GI tract toward the colon (61, 63). NKp44+ ILC3s, which represent the main producers of IL-22 among the ILC3 subsets (91), are the most abundant helper subset in the human intestine (612), whereas ILC2s are barely detectable (61, 63, 92). GI infection and inflammation are associated with significantly altered distribution of helper ILCs, indicating a role for these populations in both pathogen control and inflammatory diseases. We will focus on the role of helper ILCs in intestinal infection, inflammation, and cancer.

ILCs in the intestine play an essential role in the first line of defense against multiple pathogens by quickly releasing soluble factors and regulating subsequent adaptive responses. ILCs, in particular ILC3s, are also needed for an optimal symbiotic relationship with the microbiota, as discussed in detail elsewhere (93). Lack of ILCs leads to dysbiosis (94) and peripheral dissemination of commensal bacteria, which can be prevented by IL-22 administration (95), as this cytokine induces secretion of antimicrobial peptides (RegIIIb, RegIIIg, and the S100 family) (96). In contrast, several studies showed fewer ILC3s, or defective ILC functions, in germ-free mice (9799). These defects could be linked to the fact that ILC function is directly regulated by multiple metabolites (100, 101), including short-chain fatty acids (97, 102), whose levels change in relationship to microbiome composition.

The microbiome also regulates ILC function via other cell types, including epithelial cells, macrophages, and DCs. Human ILC1-mediated production of IFN-γ upon exposure to gut commensals or pathogens depends on myeloid DC release of IL-12p70, IL-18, and IL-1β (103). The microbiota can regulate ILC2 activity via mediators produced by intestinal epithelia cells (TSLP) or plasmacytoid DCs (type I IFNs) in a positive or negative way, respectively (104, 105). ILC3-mediated production of GM-CSF is dependent on the ability of colonic murine macrophages to sense microbial signals and produce IL-1β (106). ILC3s are the most important for the maintenance of intestinal barrier integrity, including tissue repair after infectious or inflammatory damage. ILC3-derived IL-22 promotes epithelium survival and proliferation, mucus production, and increased expression of antimicrobial peptides (95, 107110). This subset is critical against several bacterial and fungal infections.

Citrobacter rodentium infection in mice is a widely used model to mimic human attaching-and-effacing Escherichia coli infections and chronic intestinal inflammation (111). Whereas bacterial clearance requires adaptive immunity (112), ILC3-secreted IL-22 is essential in the initial phase of C. rodentium infection (99, 110), and multiple studies confirm the protective role of ILC3s (85, 95, 99, 101, 113). Several mechanisms have been described to induce or regulate ILC3 activation during C. rodentium infection, including interaction with mononuclear phagocytes (111118), engagement of ILC3 receptors, such as G protein–coupled receptors and the aryl hydrocarbon receptor (AhR) (97, 113, 119122), and sensing of metabolites such as retinoic acid, vitamin D, and short-chain fatty acids (102, 123129). Among the ILC3 receptors, AhR, a ligand-dependent transcription factor sensing environmental cues and endogenous compounds generated by commensal, dietary, or cellular metabolism (130, 131), is recognized as a key regulator of ILC3 function (101, 113, 121, 132). Additionally, it was demonstrated that ablation of Ahr enhances intestinal ILC2 function and antihelminth immunity, whereas activation of AhR suppresses ILC2 function, suggesting that the intestinal ILC2/ILC3 balance is maintained by engaging the AhR pathway to mount adequate responses against distinct pathogens (132). Two other receptors known to regulate ILC3 responses to C. rodentium are the NK molecule NKR-P1B (133, 134) and GPR183 (119, 120), whose genetic ablation results in increased susceptibility to infection (119, 134).

In terms of phagocyte-mediated activation of ILC3, multiple requirements have been identified for myeloid phagocytes to promote IL-22 secretion. Intestinal macrophages, by releasing IL-1β and IL-23, promote ILC3-mediated production of IL-22 and antimicrobial peptides such as lectins of the RegIII family (115, 116, 135). Cross-talk via CXCL16 (on macrophages) and CXCR6 (on ILC3) is needed for an effective immune response to C. rodentium infection. Similarly, β2 integrin expression on intestinal macrophages was necessary for macrophage-derived IL-1β release and optimal ILC3-mediated production of IL-22. Finally, ILC3–macrophage cross-talk, mediated by ILC3-derived GM-CSF, results in the differentiation of M1 inflammatory macrophages and the establishment of a positive feedback loop that augments ILC3 activation and Th17-type immunity (136). While this feedback loop enhances antibacterial responses, it can lead to chronic inflammation, as GM-CSF inhibits wound healing and tissue repair programs (136). Following C. rodentium infection, mice with intestinal epithelial cell–specific ablation of IKKα displayed impaired ILC3-mediated production of IL-22 and antimicrobial peptides, severe intestinal inflammation, elevated bacterial dissemination, and mortality (137). Treatment with IL-22 or transfer of ILC3s obtained from WT mice restored protection (137).

Salmonella typhimurium is a facultative intracellular bacterium that causes gastroenteritis in humans, but in mice it only establishes infection after antibiotic treatment (138). Multiple studies have demonstrated that IL-22 is needed for protection against S. typhimurium, as it contributes to shaping an adequate microenvironmental niche for commensal bacteria (139, 140). However IFN-γ, produced by both ILC1s and CCR6T-bet+RORγt+ ILCs (141, 142), is also required for protection, as it promotes the release of mucus-forming glycoproteins that shield the epithelial barrier during infection (143, 144). The antimicrobial function of ILC3 during S. typhimurium infection is regulated by Runt-related transcription factor 3 (Runx3) (142). S. typhimurium infection induced RORγt+T-bet+ ILC3 accumulation in the mesenteric lymph nodes, where they migrated from the colon, displaying elevated IFN-γ production (145). The inducible expression of T-bet in CCR6RORγt+ ILCs, which appear to have both ILC3 and ILC1 features, is consistent with data on human ILCs (67, 146), and it suggests that ILC plasticity enables a switch from a homeostatic to a proinflammatory phenotype in response to infections.

Although ILC1s are the most important ILCs for protection from Toxoplasma gondii (69), Ahr−/− mice, characterized by a pronounced ILC3 defect, following infection had more marked intestinal damage than did WT mice, possibly due to exaggerated T cells responses (147), indicating that in this model ILC3 may indirectly mitigate intestinal damage. ILC3s are also involved in protection against fungi. They were identified as the major source of IL-17 in response to C. albicans and essential for IL-17–mediated protective immunity in the oral mucosa in a murine model of oropharyngeal candidiasis (148).

ILC1s protect against a broad range of intracellular pathogens, including bacteria, viruses, and protozoa. Clostridium difficile infection can cause severe colitis and diarrhea when the normal microbiota is perturbed after antibiotic treatment (149). ILCs appear to protect against C. difficile because Nfil−/− mice, which lack all ILC subsets, succumbed within 3 d, while WT and Nfil3+/− heterozygous mice recovered (150). Consistent with these results, C. difficile infection caused an upregulation of both ILC1 (IFN-γ, TNF-α, NOS2)- and ILC3 (IL-22, IL-17A RegIII)-derived soluble factors in the intestine of Rag1−/− mice, but not in Rag1−/−Il2rg−/− mice (which lack all ILCs) (151). Rag1−/−Il2rg−/− mice displayed increased susceptibility to C. difficile, quickly succumbing to the infection; ILC transfer restored protection from infection (151). Both Rag1−/−Tbx21−/− and Rag1−/−ifng−/− mice displayed elevated C. difficile susceptibility and lethality compared with Rag1−/− mice, suggesting that protection against this pathogen is mediated mostly by the ILC1 subset (151).

ILC1s play a pathogenic role in a murine model of enterocolitis driven by Campylobacter jejuni. This common human pathogen causes gastroenteritis and may lead to long-term intestinal dysfunction such as postinfectious immune-mediated irritable bowel syndrome (152, 153). The intestine of infected mice displayed an accumulation of IFN-γ+T-bet+ ILCs, which correspond to ILC1s derived from fate mapping RORγt+ progenitors (154). Adoptive transfer of this population promoted pathology, whereas T-bet inactivation in this subset mitigated disease, consistent with the concept that IFN-γ can drive intestinal inflammation (154).

ILC1s are the key ILC subset for protection against the intracellular protozoan T. gondii. Intestinal ILC1s produce most IFN-γ as well as TNF-α and quickly attract monocytes at the site of infection. T-bet−/− mice produce no IFN-γ in response to T. gondii, fail to recruit inflammatory monocytes, and control parasite replication; however, transfer of WT ILC1s into Rag2−/−il2rg−/− mice restores infection control (69). In addition to ILC1s, T. gondii infection also induced accumulation of NK-derived ILC1-like cells that are distinct from both steady-state NK cells and ILC1s in uninfected mice (155).

ILC2s are critical in the early phase of immune responses against parasitic helminths, and a few worms are known to elicit their responses (156162). Infection with Nippostrongylus brasiliensis is a widely used, well-described experimental system for ILC2 antiparasitic function in the intestine. After helminth infection, ILC2s rapidly release abundant IL-13, driving goblet cell hyperplasia, smooth muscle hypercontractility, mucus production, eosinophil recruitment, and, ultimately, worm expulsion (73, 74, 77, 163, 164). Multiple studies confirmed the essential role of IL-13 in worm clearance, using a combination of gene-ablated mice and adoptive transfer experiments (7376). While considered mostly tissue resident, ILC2s can engage in trans-organ migration. Inflammatory ILC2s, induced from resting intestinal ILC2s by IL-25 or helminth infection, migrated from the intestine to diverse sites based on sphingosine 1-phosphate (S1P)–mediated chemotaxis (165). The inflammatory ILC2s were crucial for clearing worms and promoting tissue repair in the lung via amphiregulin secretion (165). Similarly, ILC2s migrated to the lung following infection with the intestinal nematode Trichinella spiralis, providing local cross-protection against a secondary N. brasiliensis infection (161). Generation of inflammatory ILC2s was promoted by the enzyme tryptophan hydroxylase 1 (Tph1), which was upregulated in an IL-33–dependent manner upon helminth-induced activation (166). Conditional ablation of Tph1 in lymphocytes resulted in an impairment of inflammatory ILC2 responses, with consequent increased susceptibility to helminths (166). Tph1-deficient ILC2s displayed defective activation and lower levels of ICOS, and in vivo administration of an ICOS blocking Ab after N. brasiliensis infection resulted in decreased recruitment of inflammatory ILC2s to the mesenteric lymph nodes (166).

In addition to direct effects on intestinal parasites, ILC2s also regulate the response to worm infection via interaction with CD4 T cells, with evidence indicating that ILC2 and Th2 cell responses to helminth infections are interdependent. ILC2s are needed for an efficient development of Th2 responses during N. brasiliensis infection, as their ablation resulted in significantly lower levels of CD4 T cells producing IL-5 and IL-13, with consequent delay in worm expulsion (167). A number of cognate receptors pairs are involved in the ILC2–CD4 T cell cross-talk that promotes mutual maintenance, expansion, and cytokine production (167, 168). These pairs include MCH class II-TCR (167), OX40-OX40L (168), and ICOS-ICOSL (169).

ILC2s also play a role in some bacterial and protozoan infections, including C. difficile, H. pylori, and Trichuris muris infections (170172). During C. difficile infection, IL-33 activates ILC2s, which in turn promote eosinophilia and protection from epithelial damage (170). Finally, both humans and mice infected with H. pylori display elevated ILC2s (171, 172), which appear to contribute to the IgA-mediated containment of H. pylori infection. ILC2-ablated mice exhibit increased gastric inflammation and bleeding compared with WT mice (172).

The flip side of ILC importance for the maintenance of epithelial integrity and tissue homeostasis is their association with inflammatory disorders, including CD and UC, the two most common forms of IBD. ILC function in intestinal inflammation was first investigated in mouse models of IBD (84, 99, 100, 173), which identified a protective role for ILC3-derived IL-22 (99, 100, 173). Two early investigations of CD patients provided clear evidence of the implication of ILCs in human intestinal inflammation, although these studies did not use current definitions of ILC subsets (174, 175). Later investigations confirmed a decrease of ILC3 frequency in the lamina propria of IBD patients, with a concomitant accumulation of ILC1s (67, 176, 177). The decrease in NKp44+ ILC3 frequencies, detected in inflamed intestinal tissue but not in non-diseased tissue, was associated with disease severity in both CD and UC (61). A comparison of IBD patients enrolled at diagnosis and individuals with established disease showed that NKp44+ ILC3 levels were already low at diagnosis, suggesting that their decrease is a contributing factor to the chronic inflammatory state, rather than its consequence (61). Treatment of IBD patients with monoclonal Abs of known therapeutic efficacy partially restored the healthy equilibrium between intestinal ILC subsets, suggesting that rebalancing intestinal ILCs may contribute to beneficial effects of the biologics (177). Unlike the NKp44+ subset, NKp44 ILC3s, which produce IL-17 and IFN-γ, contribute to IBD immunopathology, as suggested by several studies in murine models and IBD patients (61, 84, 176, 178). In UC patients the increase of NKp44 ILCs directly correlated with disease severity (61).

ILC1s are pathogenic in chronic intestinal inflammation. Multiple studies, both in mouse models and human patients, observed elevated ILC1 levels in lamina propria and epithelium of diseased intestine, with ILC1-derived IFN-γ driving the inflammatory process (61, 67, 68, 177, 179) and its neutralization ameliorating disease progression (85). ILC2s, present at low frequencies in healthy human intestine (61, 63), were increased in UC patients at diagnosis and in both CD and UC patients with established disease (61).

The unbalanced distribution of ILC subsets in the intestinal mucosa of IBD patients is partly explained by ILC plasticity, which appears to contribute to IBD pathogenesis. The accumulation of ILC1s in the intestine of IBD patients is likely exacerbated by the transdifferentiation of both ILC2s and ILC3s into ILC1s in the presence of elevated levels of IL-12, described in vitro (66, 67, 146, 180183). ILC3 to ILC1 transdifferentiation is associated with increased expression of Aiolos, a transcription factor elevated in ILC1s, and requires expression of Ikaros to suppress the AhR pathway (182, 184, 185). Suppression of Aiolos and Ikaros inhibited in vitro transdifferentiation of tonsillar ILC3s into ILC1s, while preserving ILC3 function (182). Transdifferentiation of ILC1s into ILC3s upon exposure to IL-2, IL-23, and IL-1β was also observed, both in vitro and in vivo, and was accelerated in the presence of retinoic acid (146). In support of the notion that ILC transdifferentiation happens in vivo and has physiological relevance, elevated intestinal levels of IL-12 were reported in CD patients (175, 186) in whom an inverse relationship between the NKp44+ ILC3 and ILC1 frequencies was also observed (61, 67, 177, 187). Additionally, RNA velocity analysis of human tonsil ILCs revealed the presence of an intermediate ILC3-ILC1 cluster with multiple subsets, while ILC3 and ILC1 represented the ends of the spectrum (184). A transitional ILC3-ILC1 population, coexpressing both ILC3 and ILC1 signature genes, was also observed in the lamina propria of human ileum (184). Finally, the presence of IFN-γ+ “ex-ILC2s” in the intestine of CD patients suggests that ILC2-to-ILC1 transitions also occur in vivo (181). Overall, ILC transdifferentiation in the intestinal mucosa of IBD patients appears to contribute to an unbalanced and pathogenic ILC composition, and it may be a factor of clinical significance in the context of cancer.

The presence of ILCs has been detected in multiple types of cancer (188), and evidence for both anti- and pro-tumorigenic roles has been described for all helper ILCs. The conflicting evidence may be explained by their heterogeneity in terms of function, ontogeny, and location combined with differences in cancer microenvironment (189)

ILC1s, secreting abundant IFN-γ and TNF-α, are a recognized driver of chronic intestinal inflammation, and they may thus promote malignant transformation (190). ILC2s and ILC3s converting to ILC1s in the presence of elevated IL-12 are likely to exacerbate the inflammatory conditions. However, IFN-γ and TNF-α also have well-described anti-cancer functions, which include promoting the accumulation of tumor-infiltrating macrophages and DCs, recruiting and activating effector cells (such as NK and CD8 T cells) to promote their cytotoxic activity, inhibiting angiogenesis, and impairing survival of cancer cells and inducing their apoptosis (191, 192). The outcome of the integration of ILC1 pro- and anti-tumorigenic function is likely to depend on the microenvironment at the lesion site.

There is scarce direct evidence of a role of ILC2s in intestinal cancer. More data are available about the cytokines IL-33 and IL-13. IL-33 appears to contribute to carcinogenesis in multiple ways, due to its ability to modulate angiogenesis and stromal remodeling. In particular, IL-33 was involved in the development of intestinal cancer in two murine models, promoting IL-6 secretion and activation of stromal cells (193, 194). Analysis of human tumors suggests a more pronounced role for IL-33 in the early stage of tumorigenesis (194). Other studies, however, have described the anti-tumor effects of IL-33. Low expression levels or ablation of ST2L, one of the IL-33 receptor isoforms, were associated, respectively, with cancer tissue in humans and enhanced tumor growth in a murine model of colon cancer (195). Moreover, treatment with IL-33 reduced tumor growth in an eosinophil-depended manner (196), suggesting that the IL-33 effect was mediated by ILC2-derived IL-5. The ILC2/IL-13 axis is thought to be involved in the establishment of a protumorigenic milieu, as ILC2-derived IL-13 promotes the recruitment and activity of myeloid derived suppressor cells (197, 198); additionally, high expression of IL-13Ra was associated with poor prognosis (179). However, recent evidence supports a protective role of ILC2s in colon cancer in mice and humans, with ILC2 ablation or blockade resulting in increased tumor burden (199, 200). In humans, high expression of an intratumor ILC2 gene signature was associated with increased survival, possibly due to IL-9–mediated activation of CD8 T cells (200).

Most of the evidence about ILC3 cells indicates that they may play a role in the initiation and progression of colorectal cancer. In human cancers, elevated expression of IL-23 and IL-23R in malignant tissue was associated with progression to fatal metastatic disease (201, 202). Mice with IL-23p19 chain or ILC ablation were protected from intestinal tumorigenesis induced by systemic overexpression of IL-23 (201, 202). Multiple studies showed a pro-tumorigenic effect of ILC3-derived IL-22 in murine and human colon cancer: ILC ablation, IL-22 neutralization, and factors attenuating IL-22 secretion (e.g., lack of Card9) were associated with protective effects (203206). Conversely, IL-22 secretion induced by C. albicans accumulation in the intestine of dectin-3–deficient mice resulted in tumor progression (207). Evidence pointing toward a protective role of ILC3 was obtained in cases of non-small cell lung cancer and melanoma (208, 209), and in a murine model of colon cancer (210). Finally, in a study of human colon cancer, the numbers of ILC3s and NKp44+ ILC3s in tumor tissue were lower than those in distal regions and were negatively correlated with cancer stage, in agreement with previous reports (211, 212).

NKT cells and ILCs are important constituents in the maintenance of mucosal homeostasis (213). As highlighted in (Fig. 1, communication between the gut microbiota, NKT cells, and ILCs is crucial for intestinal homeostasis. iNKT cells are regulated by commensals and they can in turn modulate the functions of other immune cells, such as ILC3s, regulatory T cells, and conventional T cell subsets. ILC3s can produce IL-22, thereby contributing to intestinal homeostasis. Conversely, in certain situations, subsets of NKT cells and ILCs can drive intestinal inflammation, most notably through IL-13–dependent mechanisms, which can have pathological consequences. Collectively, these nonconventional lymphocyte subpopulations influence the composition of the intestinal microbiota in a bidirectional manner, which makes them attractive candidates for therapeutic intervention in the context of infection, chronic inflammatory disorders, and colorectal cancer. However, much more work is needed to determine how to effectively modulate the desired subset of NKT cells and ILCs to develop treatment strategies. Thus, future studies utilizing single-cell RNA sequencing and proteomic approaches to investigate host–microbe interactions will be critical to advance our understanding and move the field forward.

FIGURE 1.

NKT cells and ILCs play a critical role in intestinal homeostasis. Intestinal iNKT cells can be activated by lipids presented by DCs. Activated iNKT cells regulate the function of other immune cells and commensals, in part through their production of cytokines, such as IFN-γ and IL-4. Interactions with ILC3s results in their production of IL-22, which also contributes to intestinal homeostasis. However, NKT cells can contribute to intestinal inflammation through their production of IL-13. IL-13 can induce apoptosis of intestinal epithelial cells, which can lead to loss of barrier function. Created with BioRender.com.

FIGURE 1.

NKT cells and ILCs play a critical role in intestinal homeostasis. Intestinal iNKT cells can be activated by lipids presented by DCs. Activated iNKT cells regulate the function of other immune cells and commensals, in part through their production of cytokines, such as IFN-γ and IL-4. Interactions with ILC3s results in their production of IL-22, which also contributes to intestinal homeostasis. However, NKT cells can contribute to intestinal inflammation through their production of IL-13. IL-13 can induce apoptosis of intestinal epithelial cells, which can lead to loss of barrier function. Created with BioRender.com.

Close modal

There are many groups examining the role of NKT cells and ILCs in intestinal homeostasis, and we apologize to those whose work may have been omitted due to space considerations. The schematic in Fig. 1 was created with BioRender.com.

T.J.W. was supported by U.S. Department of Health and Human Services/National Institutes of Health Grants P30CA134274 and R25GM113262.

Abbreviations used in this article

AhR

aryl hydrocarbon receptor

CD

Crohn’s disease

DC

dendritic cell

αGalCer

α‐galactosylceramide

GI

gastrointestinal

IBD

inflammatory bowel disease

ILC

innate lymphoid cell

iNKT

invariant NKT

LPMC

lamina propria mononuclear cell

ROR

retinoic acid–related orphan receptor

Tph1

tryptophan hydroxylase 1

TSLP

stromal lymphopoietin

UC

ulcerative colitis

WT

wild-type

1.
Hooper
L. V.
,
D. R.
Littman
,
A. J.
Macpherson
.
2012
.
Interactions between the microbiota and the immune system.
Science
336
:
1268
1273
.
2.
Makino
Y.
,
R.
Kanno
,
T.
Ito
,
K.
Higashino
,
M.
Taniguchi
.
1995
.
Predominant expression of invariant Vα14+ TCR α chain in NK1.1+ T cell populations.
Int. Immunol.
7
:
1157
1161
.
3.
Fowlkes
B. J.
,
A. M.
Kruisbeek
,
H.
Ton-That
,
M. A.
Weston
,
J. E.
Coligan
,
R. H.
Schwartz
,
D. M.
Pardoll
.
1987
.
A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vβ gene family.
Nature
329
:
251
254
.
4.
Godfrey
D. I.
,
S.
Stankovic
,
A. G.
Baxter
.
2010
.
Raising the NKT cell family.
Nat. Immunol.
11
:
197
206
.
5.
Godfrey
D. I.
,
A. P.
Uldrich
,
J.
McCluskey
,
J.
Rossjohn
,
D. B.
Moody
.
2015
.
The burgeoning family of unconventional T cells. [Published errata appear in 2016 Nat. Immunol. 17: 214 and 2016 Nat. Immunol. 469.]
Nat. Immunol.
16
:
1114
1123
.
6.
Lee
Y. J.
,
H.
Wang
,
G. J.
Starrett
,
V.
Phuong
,
S. C.
Jameson
,
K. A.
Hogquist
.
2015
.
Tissue-specific distribution of iNKT cells impacts their cytokine response.
Immunity
43
:
566
578
.
7.
Lee
Y. J.
,
K. L.
Holzapfel
,
J.
Zhu
,
S. C.
Jameson
,
K. A.
Hogquist
.
2013
.
Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. [Published erratum appears in 2014 Nat. Immunol. 15: 305.]
Nat. Immunol.
14
:
1146
1154
.
8.
Uldrich
A. P.
,
O.
Patel
,
G.
Cameron
,
D. G.
Pellicci
,
E. B.
Day
,
L. C.
Sullivan
,
K.
Kyparissoudis
,
L.
Kjer-Nielsen
,
J. P.
Vivian
,
B.
Cao
, et al
2011
.
A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen-recognition properties.
Nat. Immunol.
12
:
616
623
.
9.
Brigl
M.
,
P.
van den Elzen
,
X.
Chen
,
J. H.
Meyers
,
D.
Wu
,
C.-H.
Wong
,
F.
Reddington
,
P. A.
Illarianov
,
G. S.
Besra
,
M. B.
Brenner
,
J. E.
Gumperz
.
2006
.
Conserved and heterogeneous lipid antigen specificities of CD1d-restricted NKT cell receptors.
J. Immunol.
176
:
3625
3634
.
10.
Gadola
S. D.
,
N.
Dulphy
,
M.
Salio
,
V.
Cerundolo
.
2002
.
Vα24-JαQ-independent, CD1d-restricted recognition of α-galactosylceramide by human CD4+ and CD8αβ+ T lymphocytes.
J. Immunol.
168
:
5514
5520
.
11.
López-Sagaseta
J.
,
J. E.
Kung
,
P. B.
Savage
,
J.
Gumperz
,
E. J.
Adams
.
2012
.
The molecular basis for recognition of CD1d/α-galactosylceramide by a human non-Vα24 T cell receptor.
PLoS Biol.
10
:
e1001412
.
12.
Fan
X.
,
A. Y.
Rudensky
.
2016
.
Hallmarks of tissue-resident lymphocytes.
Cell
164
:
1198
1211
.
13.
Crosby
C. M.
,
M.
Kronenberg
.
2018
.
Tissue-specific functions of invariant natural killer T cells.
Nat. Rev. Immunol.
18
:
559
574
.
14.
Thomas
S. Y.
,
S. T.
Scanlon
,
K. G.
Griewank
,
M. G.
Constantinides
,
A. K.
Savage
,
K. A.
Barr
,
F.
Meng
,
A. D.
Luster
,
A.
Bendelac
.
2011
.
PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions.
J. Exp. Med.
208
:
1179
1188
.
15.
Terabe
M.
,
J. A.
Berzofsky
.
2008
.
The role of NKT cells in tumor immunity.
Adv. Cancer Res.
101
:
277
348
.
16.
Lin
H.
,
M.
Nieda
,
J. F.
Hutton
,
V.
Rozenkov
,
A. J.
Nicol
.
2006
.
Comparative gene expression analysis of NKT cell subpopulations.
J. Leukoc. Biol.
80
:
164
173
.
17.
Gumperz
J. E.
,
S.
Miyake
,
T.
Yamamura
,
M. B.
Brenner
.
2002
.
Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining.
J. Exp. Med.
195
:
625
636
.
18.
Lee
P. T.
,
K.
Benlagha
,
L.
Teyton
,
A.
Bendelac
.
2002
.
Distinct functional lineages of human Vα24 natural killer T cells.
J. Exp. Med.
195
:
637
641
.
19.
Kim
C. H.
,
B.
Johnston
,
E. C.
Butcher
.
2002
.
Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among α24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity.
Blood
100
:
11
16
.
20.
Chang
P. P.
,
P.
Barral
,
J.
Fitch
,
A.
Pratama
,
C. S.
Ma
,
A.
Kallies
,
J. J.
Hogan
,
V.
Cerundolo
,
S. G.
Tangye
,
R.
Bittman
, et al
2011
.
Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses.
Nat. Immunol.
13
:
35
43
.
21.
King
I. L.
,
A.
Fortier
,
M.
Tighe
,
J.
Dibble
,
G. F.
Watts
,
N.
Veerapen
,
A. M.
Haberman
,
G. S.
Besra
,
M.
Mohrs
,
M. B.
Brenner
,
E. A.
Leadbetter
.
2011
.
Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner.
Nat. Immunol.
13
:
44
50
.
22.
Tonti
E.
,
M.
Fedeli
,
A.
Napolitano
,
M.
Iannacone
,
U. H.
von Andrian
,
L. G.
Guidotti
,
S.
Abrignani
,
G.
Casorati
,
P.
Dellabona
.
2012
.
Follicular helper NKT cells induce limited B cell responses and germinal center formation in the absence of CD4+ T cell help.
J. Immunol.
188
:
3217
3222
.
23.
Lynch
L.
,
X.
Michelet
,
S.
Zhang
,
P. J.
Brennan
,
A.
Moseman
,
C.
Lester
,
G.
Besra
,
E. E.
Vomhof-Dekrey
,
M.
Tighe
,
H.-F.
Koay
, et al
2015
.
Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of Treg cells and macrophages in adipose tissue.
Nat. Immunol.
16
:
85
95
.
24.
Sag
D.
,
P.
Krause
,
C. C.
Hedrick
,
M.
Kronenberg
,
G.
Wingender
.
2014
.
IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset.
J. Clin. Invest.
124
:
3725
3740
.
25.
Brennan
P. J.
,
M.
Brigl
,
M. B.
Brenner
.
2013
.
Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions.
Nat. Rev. Immunol.
13
:
101
117
.
26.
Brutkiewicz
R. R.
2006
.
CD1d ligands: the good, the bad, and the ugly.
J. Immunol.
177
:
769
775
.
27.
Georgiev
H.
,
I.
Ravens
,
C.
Benarafa
,
R.
Förster
,
G.
Bernhardt
.
2016
.
Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets.
Nat. Commun.
7
:
13116
.
28.
Lee
Y. J.
,
G. J.
Starrett
,
S. T.
Lee
,
R.
Yang
,
C. M.
Henzler
,
S. C.
Jameson
,
K. A.
Hogquist
.
2016
.
Lineage-specific effector signatures of invariant NKT cells are shared amongst γδ T, innate lymphoid, and Th cells.
J. Immunol.
197
:
1460
1470
.
29.
Marrero
I.
,
I.
Maricic
,
A. E.
Feldstein
,
R.
Loomba
,
B.
Schnabl
,
J.
Rivera-Nieves
,
L.
Eckmann
,
V.
Kumar
.
2018
.
Complex network of NKT cell subsets controls immune homeostasis in liver and gut.
Front. Immunol.
9
:
2082
.
30.
Brailey
P. M.
,
M.
Lebrusant-Fernandez
,
P.
Barral
.
2020
.
NKT cells and the regulation of intestinal immunity: a two-way street.
FEBS J.
287
:
1686
1699
.
31.
Riffelmacher
T.
,
M.
Kronenberg
.
2020
.
Metabolic triggers of invariant natural killer T-cell activation during sterile autoinflammatory disease.
Crit. Rev. Immunol.
40
:
367
378
.
32.
Olszak
T.
,
D.
An
,
S.
Zeissig
,
M. P.
Vera
,
J.
Richter
,
A.
Franke
,
J. N.
Glickman
,
R.
Siebert
,
R. M.
Baron
,
D. L.
Kasper
,
R. S.
Blumberg
.
2012
.
Microbial exposure during early life has persistent effects on natural killer T cell function.
Science
336
:
489
493
.
33.
Wingender
G.
,
D.
Stepniak
,
P.
Krebs
,
L.
Lin
,
S.
McBride
,
B.
Wei
,
J.
Braun
,
S. K.
Mazmanian
,
M.
Kronenberg
.
2012
.
Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice.
Gastroenterology
143
:
418
428
.
34.
Wei
B.
,
G.
Wingender
,
D.
Fujiwara
,
D. Y.
Chen
,
M.
McPherson
,
S.
Brewer
,
J.
Borneman
,
M.
Kronenberg
,
J.
Braun
.
2010
.
Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells.
J. Immunol.
184
:
1218
1226
.
35.
Loh
L.
,
M. A.
Ivarsson
,
J.
Michaëlsson
,
J. K.
Sandberg
,
D. F.
Nixon
.
2014
.
Invariant natural killer T cells developing in the human fetus accumulate and mature in the small intestine.
Mucosal Immunol.
7
:
1233
1243
.
36.
An
D.
,
S. F.
Oh
,
T.
Olszak
,
J. F.
Neves
,
F. Y.
Avci
,
D.
Erturk-Hasdemir
,
X.
Lu
,
S.
Zeissig
,
R. S.
Blumberg
,
D. L.
Kasper
.
2014
.
Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells.
Cell
156
:
123
133
.
37.
Liu
Q.
,
C. H.
Kim
.
2019
.
Control of tissue-resident invariant NKT cells by vitamin A metabolites and P2X7-mediated cell death.
J. Immunol.
203
:
1189
1197
.
38.
Nieuwenhuis
E. E.
,
T.
Matsumoto
,
D.
Lindenbergh
,
R.
Willemsen
,
A.
Kaser
,
Y.
Simons-Oosterhuis
,
S.
Brugman
,
K.
Yamaguchi
,
H.
Ishikawa
,
Y.
Aiba
, et al
2009
.
Cd1d-dependent regulation of bacterial colonization in the intestine of mice.
J. Clin. Invest.
119
:
1241
1250
.
39.
Macho-Fernandez
E.
,
M.
Brigl
.
2015
.
The extended family of CD1d-restricted NKT cells: sifting through a mixed bag of TCRs, antigens, and functions.
Front. Immunol.
6
:
362
.
40.
Gumperz
J. E.
,
C.
Roy
,
A.
Makowska
,
D.
Lum
,
M.
Sugita
,
T.
Podrebarac
,
Y.
Koezuka
,
S. A.
Porcelli
,
S.
Cardell
,
M. B.
Brenner
,
S. M.
Behar
.
2000
.
Murine CD1d-restricted T cell recognition of cellular lipids.
Immunity
12
:
211
221
.
41.
Kawano
T.
,
J.
Cui
,
Y.
Koezuka
,
I.
Toura
,
Y.
Kaneko
,
K.
Motoki
,
H.
Ueno
,
R.
Nakagawa
,
H.
Sato
,
E.
Kondo
, et al
1997
.
CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides.
Science
278
:
1626
1629
.
42.
Wieland Brown
L. C.
,
C.
Penaranda
,
P. C.
Kashyap
,
B. B.
Williams
,
J.
Clardy
,
M.
Kronenberg
,
J. L.
Sonnenburg
,
L. E.
Comstock
,
J. A.
Bluestone
,
M. A.
Fischbach
.
2013
.
Production of α-galactosylceramide by a prominent member of the human gut microbiota.
PLoS Biol.
11
:
e1001610
.
43.
von Gerichten
J.
,
K.
Schlosser
,
D.
Lamprecht
,
I.
Morace
,
M.
Eckhardt
,
D.
Wachten
,
R.
Jennemann
,
H. J.
Gröne
,
M.
Mack
,
R.
Sandhoff
.
2017
.
Diastereomer-specific quantification of bioactive hexosylceramides from bacteria and mammals.
J. Lipid Res.
58
:
1247
1258
.
44.
von Gerichten
J.
,
D.
Lamprecht
,
L.
Opálka
,
D.
Soulard
,
C.
Marsching
,
R.
Pilz
,
V.
Sencio
,
S.
Herzer
,
B.
Galy
,
V.
Nordström
, et al
2019
.
Bacterial immunogenic α-galactosylceramide identified in the murine large intestine: dependency on diet and inflammation.
J. Lipid Res.
60
:
1892
1904
.
45.
Sriram
V.
,
W.
Du
,
J.
Gervay-Hague
,
R. R.
Brutkiewicz
.
2005
.
Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells.
Eur. J. Immunol.
35
:
1692
1701
.
46.
Kinjo
Y.
,
E.
Tupin
,
D.
Wu
,
M.
Fujio
,
R.
Garcia-Navarro
,
M. R.-E.-I.
Benhnia
,
D. M.
Zajonc
,
G.
Ben-Menachem
,
G. D.
Ainge
,
G. F.
Painter
, et al
2006
.
Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria.
Nat. Immunol.
7
:
978
986
.
47.
Kinjo
Y.
,
D.
Wu
,
G.
Kim
,
G.-W.
Xing
,
M. A.
Poles
,
D. D.
Ho
,
M.
Tsuji
,
K.
Kawahara
,
C.-H.
Wong
,
M.
Kronenberg
.
2005
.
Recognition of bacterial glycosphingolipids by natural killer T cells.
Nature
434
:
520
525
.
48.
Mattner
J.
,
K. L.
Debord
,
N.
Ismail
,
R. D.
Goff
,
C.
Cantu
III
,
D.
Zhou
,
P.
Saint-Mezard
,
V.
Wang
,
Y.
Gao
,
N.
Yin
, et al
2005
.
Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. [Published erratum appears in 2006 Nature 439: 502.]
Nature
434
:
525
529
.
49.
Kinjo
Y.
,
P.
Illarionov
,
J. L.
Vela
,
B.
Pei
,
E.
Girardi
,
X.
Li
,
Y.
Li
,
M.
Imamura
,
Y.
Kaneko
,
A.
Okawara
, et al
2011
.
Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria.
Nat. Immunol.
12
:
966
974
.
50.
Chang
Y. J.
,
H. Y.
Kim
,
L. A.
Albacker
,
H. H.
Lee
,
N.
Baumgarth
,
S.
Akira
,
P. B.
Savage
,
S.
Endo
,
T.
Yamamura
,
J.
Maaskant
, et al
2011
.
Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity.
J. Clin. Invest.
121
:
57
69
.
51.
Cohen
N. R.
,
R. V.
Tatituri
,
A.
Rivera
,
G. F.
Watts
,
E. Y.
Kim
,
A.
Chiba
,
B. B.
Fuchs
,
E.
Mylonakis
,
G. S.
Besra
,
S. M.
Levitz
, et al
2011
.
Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi.
Cell Host Microbe
10
:
437
450
.
52.
Albacker
L. A.
,
V.
Chaudhary
,
Y.-J.
Chang
,
H. Y.
Kim
,
Y.-T.
Chuang
,
M.
Pichavant
,
R. H.
DeKruyff
,
P. B.
Savage
,
D. T.
Umetsu
.
2013
.
Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity.
Nat. Med.
19
:
1297
1304
.
53.
Round
J. L.
,
S. K.
Mazmanian
.
2009
.
The gut microbiota shapes intestinal immune responses during health and disease. [Published erratum appears in 2009 Nat. Rev. Immunol. 9: 600.]
Nat. Rev. Immunol.
9
:
313
323
.
54.
Heller
F.
,
I. J.
Fuss
,
E. E.
Nieuwenhuis
,
R. S.
Blumberg
,
W.
Strober
.
2002
.
Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells.
Immunity
17
:
629
638
.
55.
Fuss
I. J.
,
B.
Joshi
,
Z.
Yang
,
H.
Degheidy
,
S.
Fichtner-Feigl
,
H.
de Souza
,
F.
Rieder
,
F.
Scaldaferri
,
A.
Schirbel
,
M.
Scarpa
, et al
2014
.
IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis.
Gut
63
:
1728
1736
.
56.
Liao
C.-M.
,
M. I.
Zimmer
,
S.
Shanmuganad
,
H.-T.
Yu
,
S. L.
Cardell
,
C.-R.
Wang
.
2012
.
dysregulation of CD1d-restricted type II natural killer T cells leads to spontaneous development of colitis in mice.
Gastroenterology
142
:
326
334.e1-2
.
57.
Wang
Y.
,
S. L.
Cardell
.
2018
.
The yin and yang of invariant natural killer T cells in tumor immunity-suppression of tumor immunity in the intestine.
Front. Immunol.
8
:
1945
.
58.
Wang
Y.
,
S.
Sedimbi
,
L.
Löfbom
,
A. K.
Singh
,
S. A.
Porcelli
,
S. L.
Cardell
.
2018
.
Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells.
Mucosal Immunol.
11
:
131
143
.
59.
Tachibana
T.
,
H.
Onodera
,
T.
Tsuruyama
,
A.
Mori
,
S.
Nagayama
,
H.
Hiai
,
M.
Imamura
.
2005
.
Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas.
Clin. Cancer Res.
11
:
7322
7327
.
60.
Vivier
E.
,
D.
Artis
,
M.
Colonna
,
A.
Diefenbach
,
J. P.
Di Santo
,
G.
Eberl
,
S.
Koyasu
,
R. M.
Locksley
,
A. N. J.
McKenzie
,
R. E.
Mebius
, et al
2018
.
Innate lymphoid cells: 10 years on.
Cell
174
:
1054
1066
.
61.
Forkel
M.
,
S.
van Tol
,
C.
Höög
,
J.
Michaëlsson
,
S.
Almer
,
J.
Mjösberg
.
2019
.
Distinct alterations in the composition of mucosal innate lymphoid cells in newly diagnosed and established Crohn’s disease and ulcerative colitis.
J. Crohn’s Colitis
13
:
67
78
.
62.
Gasteiger
G.
,
X.
Fan
,
S.
Dikiy
,
S. Y.
Lee
,
A. Y.
Rudensky
.
2015
.
Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.
Science
350
:
981
985
.
63.
Krämer
B.
,
F.
Goeser
,
P.
Lutz
,
A.
Glässner
,
C.
Boesecke
,
C.
Schwarze-Zander
,
D.
Kaczmarek
,
H. D.
Nischalke
,
V.
Branchi
,
S.
Manekeller
, et al
2017
.
Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy.
PLoS Pathog.
13
:
e1006373
.
64.
Klose
C. S.
,
D.
Artis
.
2016
.
Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis.
Nat. Immunol.
17
:
765
774
.
65.
Spits
H.
,
D.
Artis
,
M.
Colonna
,
A.
Diefenbach
,
J. P.
Di Santo
,
G.
Eberl
,
S.
Koyasu
,
R. M.
Locksley
,
A. N.
McKenzie
,
R. E.
Mebius
, et al
2013
.
Innate lymphoid cells—a proposal for uniform nomenclature.
Nat. Rev. Immunol.
13
:
145
149
.
66.
Bal
S. M.
,
J. H.
Bernink
,
M.
Nagasawa
,
J.
Groot
,
M. M.
Shikhagaie
,
K.
Golebski
,
C. M.
van Drunen
,
R.
Lutter
,
R. E.
Jonkers
,
P.
Hombrink
, et al
2016
.
IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs.
Nat. Immunol.
17
:
636
645
.
67.
Bernink
J. H.
,
C. P.
Peters
,
M.
Munneke
,
A. A.
te Velde
,
S. L.
Meijer
,
K.
Weijer
,
H. S.
Hreggvidsdottir
,
S. E.
Heinsbroek
,
N.
Legrand
,
C. J.
Buskens
, et al
2013
.
Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues.
Nat. Immunol.
14
:
221
229
.
68.
Fuchs
A.
,
W.
Vermi
,
J. S.
Lee
,
S.
Lonardi
,
S.
Gilfillan
,
R. D.
Newberry
,
M.
Cella
,
M.
Colonna
.
2013
.
Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.
Immunity
38
:
769
781
.
69.
Klose
C. S. N.
,
M.
Flach
,
L.
Möhle
,
L.
Rogell
,
T.
Hoyler
,
K.
Ebert
,
C.
Fabiunke
,
D.
Pfeifer
,
V.
Sexl
,
D.
Fonseca-Pereira
, et al
2014
.
Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.
Cell
157
:
340
356
.
70.
Weizman
O. E.
,
N. M.
Adams
,
I. S.
Schuster
,
C.
Krishna
,
Y.
Pritykin
,
C.
Lau
,
M. A.
Degli-Esposti
,
C. S.
Leslie
,
J. C.
Sun
,
T. E.
O’Sullivan
.
2017
.
ILC1 confer early host protection at initial sites of viral infection.
Cell
171
:
795
808.e12
.
71.
Mjösberg
J. M.
,
S.
Trifari
,
N. K.
Crellin
,
C. P.
Peters
,
C. M.
van Drunen
,
B.
Piet
,
W. J.
Fokkens
,
T.
Cupedo
,
H.
Spits
.
2011
.
Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.
Nat. Immunol.
12
:
1055
1062
.
72.
Monticelli
L. A.
,
G. F.
Sonnenberg
,
M. C.
Abt
,
T.
Alenghat
,
C. G.
Ziegler
,
T. A.
Doering
,
J. M.
Angelosanto
,
B. J.
Laidlaw
,
C. Y.
Yang
,
T.
Sathaliyawala
, et al
2011
.
Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.
Nat. Immunol.
12
:
1045
1054
.
73.
Moro
K.
,
T.
Yamada
,
M.
Tanabe
,
T.
Takeuchi
,
T.
Ikawa
,
H.
Kawamoto
,
J.
Furusawa
,
M.
Ohtani
,
H.
Fujii
,
S.
Koyasu
.
2010
.
Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells.
Nature
463
:
540
544
.
74.
Neill
D. R.
,
S. H.
Wong
,
A.
Bellosi
,
R. J.
Flynn
,
M.
Daly
,
T. K.
Langford
,
C.
Bucks
,
C. M.
Kane
,
P. G.
Fallon
,
R.
Pannell
, et al
2010
.
Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.
Nature
464
:
1367
1370
.
75.
Price
A. E.
,
H. E.
Liang
,
B. M.
Sullivan
,
R. L.
Reinhardt
,
C. J.
Eisley
,
D. J.
Erle
,
R. M.
Locksley
.
2010
.
Systemically dispersed innate IL-13-expressing cells in type 2 immunity.
Proc. Natl. Acad. Sci. USA
107
:
11489
11494
.
76.
Saenz
S. A.
,
M. C.
Siracusa
,
J. G.
Perrigoue
,
S. P.
Spencer
,
J. F.
Urban
Jr.
,
J. E.
Tocker
,
A. L.
Budelsky
,
M. A.
Kleinschek
,
R. A.
Kastelein
,
T.
Kambayashi
, et al
2010
.
IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses.
Nature
464
:
1362
1366
.
77.
Turner
J. E.
,
P. J.
Morrison
,
C.
Wilhelm
,
M.
Wilson
,
H.
Ahlfors
,
J. C.
Renauld
,
U.
Panzer
,
H.
Helmby
,
B.
Stockinger
.
2013
.
IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation.
J. Exp. Med.
210
:
2951
2965
.
78.
Kim
B. S.
,
M. C.
Siracusa
,
S. A.
Saenz
,
M.
Noti
,
L. A.
Monticelli
,
G. F.
Sonnenberg
,
M. R.
Hepworth
,
A. S.
Van Voorhees
,
M. R.
Comeau
,
D.
Artis
.
2013
.
TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
Sci. Transl. Med.
5
:
170ra16
.
79.
Bando
J. K.
,
S.
Gilfillan
,
B.
Di Luccia
,
J. L.
Fachi
,
C.
Sécca
,
M.
Cella
,
M.
Colonna
.
2020
.
ILC2s are the predominant source of intestinal ILC-derived IL-10.
J. Exp. Med.
217
:
e20191520
.
80.
Golebski
K.
,
J. A.
Layhadi
,
U.
Sahiner
,
E. H.
Steveling-Klein
,
M. M.
Lenormand
,
R. C. Y.
Li
,
S. M.
Bal
,
B. A.
Heesters
,
G.
Vilà-Nadal
,
O.
Hunewald
, et al
2021
.
Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response.
Immunity
54
:
291
307.e7
.
81.
Huang
Q.
,
X.
Ma
,
Y.
Wang
,
Z.
Niu
,
R.
Wang
,
F.
Yang
,
M.
Wu
,
G.
Liang
,
P.
Rong
,
H.
Wang
, et al
2020
.
IL-10 producing type 2 innate lymphoid cells prolong islet allograft survival.
EMBO Mol. Med.
12
:
e12305
.
82.
Seehus
C. R.
,
A.
Kadavallore
,
B.
Torre
,
A. R.
Yeckes
,
Y.
Wang
,
J.
Tang
,
J.
Kaye
.
2017
.
Alternative activation generates IL-10 producing type 2 innate lymphoid cells.
Nat. Commun.
8
:
1900
.
83.
Wang
S.
,
P.
Xia
,
Y.
Chen
,
Y.
Qu
,
Z.
Xiong
,
B.
Ye
,
Y.
Du
,
Y.
Tian
,
Z.
Yin
,
Z.
Xu
,
Z.
Fan
.
2017
.
Regulatory innate lymphoid cells control innate intestinal inflammation.
Cell
171
:
201
216.e18
.
84.
Buonocore
S.
,
P. P.
Ahern
,
H. H.
Uhlig
,
I. I.
Ivanov
,
D. R.
Littman
,
K. J.
Maloy
,
F.
Powrie
.
2010
.
Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
Nature
464
:
1371
1375
.
85.
Cella
M.
,
A.
Fuchs
,
W.
Vermi
,
F.
Facchetti
,
K.
Otero
,
J. K.
Lennerz
,
J. M.
Doherty
,
J. C.
Mills
,
M.
Colonna
.
2009
.
A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.
Nature
457
:
722
725
.
86.
Cupedo
T.
,
N. K.
Crellin
,
N.
Papazian
,
E. J.
Rombouts
,
K.
Weijer
,
J. L.
Grogan
,
W. E.
Fibbe
,
J. J.
Cornelissen
,
H.
Spits
.
2009
.
Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells.
Nat. Immunol.
10
:
66
74
.
87.
Sawa
S.
,
M.
Lochner
,
N.
Satoh-Takayama
,
S.
Dulauroy
,
M.
Bérard
,
M.
Kleinschek
,
D.
Cua
,
J. P.
Di Santo
,
G.
Eberl
.
2011
.
RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota.
Nat. Immunol.
12
:
320
326
.
88.
Takatori
H.
,
Y.
Kanno
,
W. T.
Watford
,
C. M.
Tato
,
G.
Weiss
,
I. I.
Ivanov
II
,
D. R.
Littman
,
J. J.
O’Shea
.
2009
.
Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22.
J. Exp. Med.
206
:
35
41
.
89.
Abidi
A.
,
T.
Laurent
,
G.
Bériou
,
L.
Bouchet-Delbos
,
C.
Fourgeux
,
C.
Louvet
,
R.
Triki-Marrakchi
,
J.
Poschmann
,
R.
Josien
,
J.
Martin
.
2020
.
Characterization of rat ILCs reveals ILC2 as the dominant intestinal subset.
Front. Immunol.
11
:
255
.
90.
Dutton
E. E.
,
A.
Camelo
,
M.
Sleeman
,
R.
Herbst
,
G.
Carlesso
,
G. T.
Belz
,
D. R.
Withers
.
2017
.
Characterisation of innate lymphoid cell populations at different sites in mice with defective T cell immunity.
Wellcome Open Res.
2
:
117
.
91.
Hoorweg
K.
,
C. P.
Peters
,
F.
Cornelissen
,
P.
Aparicio-Domingo
,
N.
Papazian
,
G.
Kazemier
,
J. M.
Mjösberg
,
H.
Spits
,
T.
Cupedo
.
2012
.
Functional differences between human NKp44 and NKp44+ RORC+ innate lymphoid cells.
Front. Immunol.
3
:
72
.
92.
Yudanin
N. A.
,
F.
Schmitz
,
A. L.
Flamar
,
J. J. C.
Thome
,
E.
Tait Wojno
,
J. B.
Moeller
,
M.
Schirmer
,
I. J.
Latorre
,
R. J.
Xavier
,
D. L.
Farber
, et al
2019
.
Spatial and temporal mapping of human innate lymphoid cells reveals elements of tissue specificity.
Immunity
50
:
505
519.e4
.
93.
Britanova
L.
,
A.
Diefenbach
.
2017
.
Interplay of innate lymphoid cells and the microbiota.
Immunol. Rev.
279
:
36
51
.
94.
Kobayashi
T.
,
B.
Voisin
,
D. Y.
Kim
,
E. A.
Kennedy
,
J. H.
Jo
,
H. Y.
Shih
,
A.
Truong
,
T.
Doebel
,
K.
Sakamoto
,
C. Y.
Cui
, et al
2019
.
Homeostatic control of sebaceous glands by innate lymphoid cells regulates commensal bacteria equilibrium.
Cell
176
:
982
997.e16
.
95.
Sonnenberg
G. F.
,
L. A.
Monticelli
,
T.
Alenghat
,
T. C.
Fung
,
N. A.
Hutnick
,
J.
Kunisawa
,
N.
Shibata
,
S.
Grunberg
,
R.
Sinha
,
A. M.
Zahm
, et al
2012
.
Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria.
Science
336
:
1321
1325
.
96.
Sonnenberg
G. F.
,
L. A.
Fouser
,
D.
Artis
.
2011
.
Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22.
Nat. Immunol.
12
:
383
390
.
97.
Chun
E.
,
S.
Lavoie
,
D.
Fonseca-Pereira
,
S.
Bae
,
M.
Michaud
,
H. R.
Hoveyda
,
G. L.
Fraser
,
C. A.
Gallini Comeau
,
J. N.
Glickman
,
M. H.
Fuller
, et al
2019
.
Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity.
Immunity
51
:
871
884.e6
.
98.
Gury-BenAri
M.
,
C. A.
Thaiss
,
N.
Serafini
,
D. R.
Winter
,
A.
Giladi
,
D.
Lara-Astiaso
,
M.
Levy
,
T. M.
Salame
,
A.
Weiner
,
E.
David
, et al
2016
.
The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome.
Cell
166
:
1231
1246.e13
.
99.
Satoh-Takayama
N.
,
C. A.
Vosshenrich
,
S.
Lesjean-Pottier
,
S.
Sawa
,
M.
Lochner
,
F.
Rattis
,
J. J.
Mention
,
K.
Thiam
,
N.
Cerf-Bensussan
,
O.
Mandelboim
, et al
2008
.
Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense.
Immunity
29
:
958
970
.
100.
Mielke
L. A.
,
S. A.
Jones
,
M.
Raverdeau
,
R.
Higgs
,
A.
Stefanska
,
J. R.
Groom
,
A.
Misiak
,
L. S.
Dungan
,
C. E.
Sutton
,
G.
Streubel
, et al
2013
.
Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation.
J. Exp. Med.
210
:
1117
1124
.
101.
Qiu
J.
,
J. J.
Heller
,
X.
Guo
,
Z. M.
Chen
,
K.
Fish
,
Y. X.
Fu
,
L.
Zhou
.
2012
.
The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.
Immunity
36
:
92
104
.
102.
Sepahi
A.
,
Q.
Liu
,
L.
Friesen
,
C. H.
Kim
.
2021
.
Dietary fiber metabolites regulate innate lymphoid cell responses.
Mucosal Immunol.
14
:
317
330
.
103.
Castleman
M. J.
,
S. M.
Dillon
,
C.
Purba
,
A. C.
Cogswell
,
M.
McCarter
,
E.
Barker
,
C.
Wilson
.
2020
.
Enteric bacteria induce IFNγ and granzyme B from human colonic group 1 innate lymphoid cells.
Gut Microbes
12
:
1667723
.
104.
Duerr
C. U.
,
C. D.
McCarthy
,
B. C.
Mindt
,
M.
Rubio
,
A. P.
Meli
,
J.
Pothlichet
,
M. M.
Eva
,
J. F.
Gauchat
,
S. T.
Qureshi
,
B. D.
Mazer
, et al
2016
.
Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells.
Nat. Immunol.
17
:
65
75
.
105.
Mosconi
I.
,
M. B.
Geuking
,
M. M.
Zaiss
,
J. C.
Massacand
,
C.
Aschwanden
,
C. K.
Kwong Chung
,
K. D.
McCoy
,
N. L.
Harris
.
2013
.
Intestinal bacteria induce TSLP to promote mutualistic T-cell responses.
Mucosal Immunol.
6
:
1157
1167
.
106.
Mortha
A.
,
A.
Chudnovskiy
,
D.
Hashimoto
,
M.
Bogunovic
,
S. P.
Spencer
,
Y.
Belkaid
,
M.
Merad
.
2014
.
Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis.
Science
343
:
1249288
.
107.
Lindemans
C. A.
,
M.
Calafiore
,
A. M.
Mertelsmann
,
M. H.
O’Connor
,
J. A.
Dudakov
,
R. R.
Jenq
,
E.
Velardi
,
L. F.
Young
,
O. M.
Smith
,
G.
Lawrence
, et al
2015
.
Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.
Nature
528
:
560
564
.
108.
Sanos
S. L.
,
V. L.
Bui
,
A.
Mortha
,
K.
Oberle
,
C.
Heners
,
C.
Johner
,
A.
Diefenbach
.
2009
.
RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.
Nat. Immunol.
10
:
83
91
.
109.
Sanos
S. L.
,
C.
Vonarbourg
,
A.
Mortha
,
A.
Diefenbach
.
2011
.
Control of epithelial cell function by interleukin-22-producing RORγt+ innate lymphoid cells.
Immunology
132
:
453
465
.
110.
Zheng
Y.
,
P. A.
Valdez
,
D. M.
Danilenko
,
Y.
Hu
,
S. M.
Sa
,
Q.
Gong
,
A. R.
Abbas
,
Z.
Modrusan
,
N.
Ghilardi
,
F. J.
de Sauvage
,
W.
Ouyang
.
2008
.
Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens.
Nat. Med.
14
:
282
289
.
111.
Eckmann
L.
2006
.
Animal models of inflammatory bowel disease: lessons from enteric infections.
Ann. N. Y. Acad. Sci.
1072
:
28
38
.
112.
Simmons
C. P.
,
S.
Clare
,
M.
Ghaem-Maghami
,
T. K.
Uren
,
J.
Rankin
,
A.
Huett
,
R.
Goldin
,
D. J.
Lewis
,
T. T.
MacDonald
,
R. A.
Strugnell
, et al
2003
.
Central role for B lymphocytes and CD4+ T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium.
Infect. Immun.
71
:
5077
5086
.
113.
Lee
J. S.
,
M.
Cella
,
K. G.
McDonald
,
C.
Garlanda
,
G. D.
Kennedy
,
M.
Nukaya
,
A.
Mantovani
,
R.
Kopan
,
C. A.
Bradfield
,
R. D.
Newberry
,
M.
Colonna
.
2011
.
AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch.
Nat. Immunol.
13
:
144
151
.
114.
Kang
L.
,
X.
Zhang
,
L.
Ji
,
T.
Kou
,
S. M.
Smith
,
B.
Zhao
,
X.
Guo
,
I.
Pineda-Torra
,
L.
Wu
,
X.
Hu
.
2020
.
The colonic macrophage transcription factor RBP-J orchestrates intestinal immunity against bacterial pathogens.
J. Exp. Med.
217
:
e20190762
.
115.
Longman
R. S.
,
G. E.
Diehl
,
D. A.
Victorio
,
J. R.
Huh
,
C.
Galan
,
E. R.
Miraldi
,
A.
Swaminath
,
R.
Bonneau
,
E. J.
Scherl
,
D. R.
Littman
.
2014
.
CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.
J. Exp. Med.
211
:
1571
1583
.
116.
Manta
C.
,
E.
Heupel
,
K.
Radulovic
,
V.
Rossini
,
N.
Garbi
,
C. U.
Riedel
,
J. H.
Niess
.
2013
.
CX3CR1+ macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium.
Mucosal Immunol.
6
:
177
188
.
117.
Satoh-Takayama
N.
,
N.
Serafini
,
T.
Verrier
,
A.
Rekiki
,
J. C.
Renauld
,
G.
Frankel
,
J. P.
Di Santo
.
2014
.
The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells.
Immunity
41
:
776
788
.
118.
Wang
B.
,
J. H.
Lim
,
T.
Kajikawa
,
X.
Li
,
B. A.
Vallance
,
N. M.
Moutsopoulos
,
T.
Chavakis
,
G.
Hajishengallis
.
2019
.
Macrophage β2-integrins regulate IL-22 by ILC3s and protect from lethal Citrobacter rodentium-induced colitis.
Cell Rep.
26
:
1614
1626.e15
.
119.
Chu
C.
,
S.
Moriyama
,
Z.
Li
,
L.
Zhou
,
A. L.
Flamar
,
C. S. N.
Klose
,
J. B.
Moeller
,
G. G.
Putzel
,
D. R.
Withers
,
G. F.
Sonnenberg
,
D.
Artis
.
2018
.
Anti-microbial functions of group 3 innate lymphoid cells in gut-associated lymphoid tissues are regulated by G-protein-coupled receptor 183.
Cell Rep.
23
:
3750
3758
.
120.
Emgård
J.
,
H.
Kammoun
,
B.
García-Cassani
,
J.
Chesné
,
S. M.
Parigi
,
J. M.
Jacob
,
H. W.
Cheng
,
E.
Evren
,
S.
Das
,
P.
Czarnewski
, et al
2018
.
Oxysterol sensing through the receptor GPR183 promotes the lymphoid-tissue-inducing function of innate lymphoid cells and colonic inflammation.
Immunity
48
:
120
132.e8
.
121.
Kiss
E. A.
,
C.
Vonarbourg
,
S.
Kopfmann
,
E.
Hobeika
,
D.
Finke
,
C.
Esser
,
A.
Diefenbach
.
2011
.
Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles.
Science
334
:
1561
1565
.
122.
Qiu
J.
,
X.
Guo
,
Z. M.
Chen
,
L.
He
,
G. F.
Sonnenberg
,
D.
Artis
,
Y. X.
Fu
,
L.
Zhou
.
2013
.
Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora.
Immunity
39
:
386
399
.
123.
Burrows
K.
,
F.
Antignano
,
A.
Chenery
,
M.
Bramhall
,
V.
Korinek
,
T. M.
Underhill
,
C.
Zaph
.
2018
.
HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis.
PLoS Pathog.
14
:
e1006869
.
124.
Chen
J.
,
A.
Waddell
,
Y. D.
Lin
,
M. T.
Cantorna
.
2015
.
Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells.
Mucosal Immunol.
8
:
618
626
.
125.
Goverse
G.
,
C.
Labao-Almeida
,
M.
Ferreira
,
R.
Molenaar
,
S.
Wahlen
,
T.
Konijn
,
J.
Koning
,
H.
Veiga-Fernandes
,
R. E.
Mebius
.
2016
.
Vitamin A controls the presence of RORγ+ innate lymphoid cells and lymphoid tissue in the small intestine.
J. Immunol.
196
:
5148
5155
.
126.
Konya
V.
,
P.
Czarnewski
,
M.
Forkel
,
A.
Rao
,
E.
Kokkinou
,
E. J.
Villablanca
,
S.
Almer
,
U.
Lindforss
,
D.
Friberg
,
C.
Höög
, et al
2018
.
Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells.
J. Allergy Clin. Immunol.
141
:
279
292
.
127.
Lin
Y. D.
,
J.
Arora
,
K.
Diehl
,
S. A.
Bora
,
M. T.
Cantorna
.
2019
.
Vitamin D is required for ILC3 derived IL-22 and protection from Citrobacter rodentium infection.
Front. Immunol.
10
:
1
.
128.
Spencer
S. P.
,
C.
Wilhelm
,
Q.
Yang
,
J. A.
Hall
,
N.
Bouladoux
,
A.
Boyd
,
T. B.
Nutman
,
J. F.
Urban
Jr.
,
J.
Wang
,
T. R.
Ramalingam
, et al
2014
.
Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity.
Science
343
:
432
437
.
129.
van de Pavert
S. A.
,
M.
Ferreira
,
R. G.
Domingues
,
H.
Ribeiro
,
R.
Molenaar
,
L.
Moreira-Santos
,
F. F.
Almeida
,
S.
Ibiza
,
I.
Barbosa
,
G.
Goverse
, et al
2014
.
Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.
Nature
508
:
123
127
.
130.
Cella
M.
,
M.
Colonna
.
2015
.
Aryl hydrocarbon receptor: linking environment to immunity.
Semin. Immunol.
27
:
310
314
.
131.
Zhou
L.
2016
.
AHR function in lymphocytes: emerging concepts.
Trends Immunol.
37
:
17
31
.
132.
Li
S.
,
J. W.
Bostick
,
J.
Ye
,
J.
Qiu
,
B.
Zhang
,
J. F.
Urban
Jr.
,
D.
Avram
,
L.
Zhou
.
2018
.
Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function.
Immunity
49
:
915
928.e5
.
133.
Rahim
M. M.
,
P.
Chen
,
A. N.
Mottashed
,
A. B.
Mahmoud
,
M. J.
Thomas
,
Q.
Zhu
,
C. G.
Brooks
,
V.
Kartsogiannis
,
M. T.
Gillespie
,
J. R.
Carlyle
,
A. P.
Makrigiannis
.
2015
.
The mouse NKR-P1B:Clr-b recognition system is a negative regulator of innate immune responses.
Blood
125
:
2217
2227
.
134.
Abou-Samra
E.
,
Z.
Hickey
,
O. A.
Aguilar
,
M.
Scur
,
A. B.
Mahmoud
,
S.
Pyatibrat
,
M. M.
Tu
,
J.
Francispillai
,
A.
Mortha
,
J. R.
Carlyle
, et al
2019
.
NKR-P1B expression in gut-associated innate lymphoid cells is required for the control of gastrointestinal tract infections.
Cell. Mol. Immunol.
16
:
868
877
.
135.
Seo
S. U.
,
P.
Kuffa
,
S.
Kitamoto
,
H.
Nagao-Kitamoto
,
J.
Rousseau
,
Y. G.
Kim
,
G.
Núñez
,
N.
Kamada
.
2015
.
Intestinal macrophages arising from CCR2+ monocytes control pathogen infection by activating innate lymphoid cells.
Nat. Commun.
6
:
8010
.
136.
Castro-Dopico
T.
,
A.
Fleming
,
T. W.
Dennison
,
J. R.
Ferdinand
,
K.
Harcourt
,
B. J.
Stewart
,
Z.
Cader
,
Z. K.
Tuong
,
C.
Jing
,
L. S. C.
Lok
, et al
2020
.
GM-CSF calibrates macrophage defense and wound healing programs during intestinal infection and inflammation.
Cell Rep.
32
:
107857
.
137.
Giacomin
P. R.
,
R. H.
Moy
,
M.
Noti
,
L. C.
Osborne
,
M. C.
Siracusa
,
T.
Alenghat
,
B.
Liu
,
K. A.
McCorkell
,
A. E.
Troy
,
G. D.
Rak
, et al
2015
.
Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity.
J. Exp. Med.
212
:
1513
1528
.
138.
Barthel
M.
,
S.
Hapfelmeier
,
L.
Quintanilla-Martínez
,
M.
Kremer
,
M.
Rohde
,
M.
Hogardt
,
K.
Pfeffer
,
H.
Rüssmann
,
W. D.
Hardt
.
2003
.
Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host.
Infect. Immun.
71
:
2839
2858
.
139.
Behnsen
J.
,
S.
Jellbauer
,
C. P.
Wong
,
R. A.
Edwards
,
M. D.
George
,
W.
Ouyang
,
M.
Raffatellu
.
2014
.
The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria.
Immunity
40
:
262
273
.
140.
Goto
Y.
,
T.
Obata
,
J.
Kunisawa
,
S.
Sato
,
I. I.
Ivanov
,
A.
Lamichhane
,
N.
Takeyama
,
M.
Kamioka
,
M.
Sakamoto
,
T.
Matsuki
, et al
2014
.
Innate lymphoid cells regulate intestinal epithelial cell glycosylation.
Science
345
:
1254009
.
141.
Klose
C. S.
,
E. A.
Kiss
,
V.
Schwierzeck
,
K.
Ebert
,
T.
Hoyler
,
Y.
d’Hargues
,
N.
Göppert
,
A. L.
Croxford
,
A.
Waisman
,
Y.
Tanriver
,
A.
Diefenbach
.
2013
.
A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells.
Nature
494
:
261
265
.
142.
Yin
S.
,
J.
Yu
,
B.
Hu
,
C.
Lu
,
X.
Liu
,
X.
Gao
,
W.
Li
,
L.
Zhou
,
J.
Wang
,
D.
Wang
, et al
2018
.
Runx3 mediates resistance to intracellular bacterial infection by promoting IL12 signaling in group 1 ILC and NCR+ILC3.
Front. Immunol.
9
:
2101
.
143.
Rhee
S. J.
,
W. A.
Walker
,
B. J.
Cherayil
.
2005
.
Developmentally regulated intestinal expression of IFN-γ and its target genes and the age-specific response to enteric Salmonella infection.
J. Immunol.
175
:
1127
1136
.
144.
Songhet
P.
,
M.
Barthel
,
B.
Stecher
,
A. J.
Müller
,
M.
Kremer
,
G. C.
Hansson
,
W. D.
Hardt
.
2011
.
Stromal IFN-γR-signaling modulates goblet cell function during Salmonella Typhimurium infection.
PLoS One
6
:
e22459
.
145.
Kästele
V.
,
J.
Mayer
,
E. S.
Lee
,
N.
Papazian
,
J. J.
Cole
,
V.
Cerovic
,
G.
Belz
,
M.
Tomura
,
G.
Eberl
,
C.
Goodyear
, et al
2021
.
Intestinal-derived ILCs migrating in lymph increase IFNγ production in response to Salmonella Typhimurium infection.
Mucosal Immunol.
14
:
717
727
.
146.
Bernink
J. H.
,
L.
Krabbendam
,
K.
Germar
,
E.
de Jong
,
K.
Gronke
,
M.
Kofoed-Nielsen
,
J. M.
Munneke
,
M. D.
Hazenberg
,
J.
Villaudy
,
C. J.
Buskens
, et al
2015
.
Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria.
Immunity
43
:
146
160
.
147.
Wagage
S.
,
G.
Harms Pritchard
,
L.
Dawson
,
E. L.
Buza
,
G. F.
Sonnenberg
,
C. A.
Hunter
.
2015
.
The group 3 innate lymphoid cell defect in aryl hydrocarbon receptor deficient mice is associated with T cell hyperactivation during intestinal infection.
PLoS One
10
:
e0128335
.
148.
Gladiator
A.
,
N.
Wangler
,
K.
Trautwein-Weidner
,
S.
LeibundGut-Landmann
.
2013
.
Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection.
J. Immunol.
190
:
521
525
.
149.
Rupnik
M.
,
M. H.
Wilcox
,
D. N.
Gerding
.
2009
.
Clostridium difficile infection: new developments in epidemiology and pathogenesis.
Nat. Rev. Microbiol.
7
:
526
536
.
150.
Geiger
T. L.
,
M. C.
Abt
,
G.
Gasteiger
,
M. A.
Firth
,
M. H.
O’Connor
,
C. D.
Geary
,
T. E.
O’Sullivan
,
M. R.
van den Brink
,
E. G.
Pamer
,
A. M.
Hanash
,
J. C.
Sun
.
2014
.
Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens.
J. Exp. Med.
211
:
1723
1731
.
151.
Abt
M. C.
,
B. B.
Lewis
,
S.
Caballero
,
H.
Xiong
,
R. A.
Carter
,
B.
Sušac
,
L.
Ling
,
I.
Leiner
,
E. G.
Pamer
.
2015
.
Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection.
Cell Host Microbe
18
:
27
37
.
152.
Al-Banna
N. A.
,
F.
Cyprian
,
M. J.
Albert
.
2018
.
Cytokine responses in campylobacteriosis: linking pathogenesis to immunity.
Cytokine Growth Factor Rev.
41
:
75
87
.
153.
O’Brien
S. J.
2017
.
The consequences of Campylobacter infection.
Curr. Opin. Gastroenterol.
33
:
14
20
.
154.
Muraoka
W. T.
,
A. A.
Korchagina
,
Q.
Xia
,
S. A.
Shein
,
X.
Jing
,
Z.
Lai
,
K. S.
Weldon
,
L. J.
Wang
,
Y.
Chen
,
L. W.
Kummer
, et al
2021
.
Campylobacter infection promotes IFNγ-dependent intestinal pathology via ILC3 to ILC1 conversion. [Published erratum appears in 2021 Mucosal Immunol. 14: 1397.]
Mucosal Immunol.
14
:
703
716
.
155.
Park
E.
,
S.
Patel
,
Q.
Wang
,
P.
Andhey
,
K.
Zaitsev
,
S.
Porter
,
M.
Hershey
,
M.
Bern
,
B.
Plougastel-Douglas
,
P.
Collins
, et al
2019
.
Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells.
eLife
8
:
e47605
.
156.
Meiners
J.
,
M.
Reitz
,
N.
Rüdiger
,
J. E.
Turner
,
L.
Heepmann
,
L.
Rudolf
,
W.
Hartmann
,
H. J.
McSorley
,
M.
Breloer
.
2020
.
IL-33 facilitates rapid expulsion of the parasitic nematode Strongyloides ratti from the intestine via ILC2- and IL-9-driven mast cell activation.
PLoS Pathog.
16
:
e1009121
.
157.
Pelly
V. S.
,
Y.
Kannan
,
S. M.
Coomes
,
L. J.
Entwistle
,
D.
Rückerl
,
B.
Seddon
,
A. S.
MacDonald
,
A.
McKenzie
,
M. S.
Wilson
.
2016
.
IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection.
Mucosal Immunol.
9
:
1407
1417
.
158.
Shimokawa
C.
,
T.
Kanaya
,
M.
Hachisuka
,
K.
Ishiwata
,
H.
Hisaeda
,
Y.
Kurashima
,
H.
Kiyono
,
T.
Yoshimoto
,
T.
Kaisho
,
H.
Ohno
.
2017
.
Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections.
Immunity
46
:
863
874.e4
.
159.
Yasuda
K.
,
M.
Matsumoto
,
K.
Nakanishi
.
2014
.
Importance of both innate immunity and acquired immunity for rapid expulsion of S. venezuelensis.
Front. Immunol.
5
:
118
.
160.
Boyd
A.
,
J. M.
Ribeiro
,
T. B.
Nutman
.
2014
.
Human CD117 (cKit)+ innate lymphoid cells have a discrete transcriptional profile at homeostasis and are expanded during filarial infection.
PLoS One
9
:
e108649
.
161.
Campbell
L.
,
M. R.
Hepworth
,
J.
Whittingham-Dowd
,
S.
Thompson
,
A. J.
Bancroft
,
K. S.
Hayes
,
T. N.
Shaw
,
B. F.
Dickey
,
A. L.
Flamar
,
D.
Artis
, et al
2019
.
ILC2s mediate systemic innate protection by priming mucus production at distal mucosal sites.
J. Exp. Med.
216
:
2714
2723
.
162.
Hurst
R. J.
,
K. J.
Else
.
2013
.
Trichuris muris research revisited: a journey through time.
Parasitology
140
:
1325
1339
.
163.
Fallon
P. G.
,
S. J.
Ballantyne
,
N. E.
Mangan
,
J. L.
Barlow
,
A.
Dasvarma
,
D. R.
Hewett
,
A.
McIlgorm
,
H. E.
Jolin
,
A. N.
McKenzie
.
2006
.
Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion.
J. Exp. Med.
203
:
1105
1116
.
164.
Zhao
A.
,
J.
McDermott
,
J. F.
Urban
Jr.
,
W.
Gause
,
K. B.
Madden
,
K. A.
Yeung
,
S. C.
Morris
,
F. D.
Finkelman
,
T.
Shea-Donohue
.
2003
.
Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves.
J. Immunol.
171
:
948
954
.
165.
Huang
Y.
,
K.
Mao
,
X.
Chen
,
M. A.
Sun
,
T.
Kawabe
,
W.
Li
,
N.
Usher
,
J.
Zhu
,
J. F.
Urban
Jr.
,
W. E.
Paul
,
R. N.
Germain
.
2018
.
S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense.
Science
359
:
114
119
.
166.
Flamar
A. L.
,
C. S. N.
Klose
,
J. B.
Moeller
,
T.
Mahlakõiv
,
N. J.
Bessman
,
W.
Zhang
,
S.
Moriyama
,
V.
Stokic-Trtica
,
L. C.
Rankin
,
G. G.
Putzel
, et al
2020
.
Interleukin-33 induces the enzyme tryptophan hydroxylase 1 to promote inflammatory group 2 innate lymphoid cell-mediated immunity.
Immunity
52
:
606
619.e6
.
167.
Oliphant
C. J.
,
Y. Y.
Hwang
,
J. A.
Walker
,
M.
Salimi
,
S. H.
Wong
,
J. M.
Brewer
,
A.
Englezakis
,
J. L.
Barlow
,
E.
Hams
,
S. T.
Scanlon
, et al
2014
.
MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion.
Immunity
41
:
283
295
.
168.
Halim
T. Y. F.
,
B. M. J.
Rana
,
J. A.
Walker
,
B.
Kerscher
,
M. D.
Knolle
,
H. E.
Jolin
,
E. M.
Serrao
,
L.
Haim-Vilmovsky
,
S. A.
Teichmann
,
H. R.
Rodewald
, et al
2018
.
Tissue-restricted adaptive type 2 immunity is orchestrated by expression of the costimulatory molecule OX40L on group 2 innate lymphoid cells.
Immunity
48
:
1195
1207.e6
.
169.
Molofsky
A. B.
,
F.
Van Gool
,
H. E.
Liang
,
S. J.
Van Dyken
,
J. C.
Nussbaum
,
J.
Lee
,
J. A.
Bluestone
,
R. M.
Locksley
.
2015
.
Interleukin-33 and interferon-γ counter-regulate group 2 innate lymphoid cell activation during immune perturbation.
Immunity
43
:
161
174
.
170.
Frisbee
A. L.
,
M. M.
Saleh
,
M. K.
Young
,
J. L.
Leslie
,
M. E.
Simpson
,
M. M.
Abhyankar
,
C. A.
Cowardin
,
J. Z.
Ma
,
P.
Pramoonjago
,
S. D.
Turner
, et al
2019
.
IL-33 drives group 2 innate lymphoid cell-mediated protection during Clostridium difficile infection.
Nat. Commun.
10
:
2712
.
171.
Li
R.
,
X. X.
Jiang
,
L. F.
Zhang
,
X. M.
Liu
,
T. Z.
Hu
,
X. J.
Xia
,
M.
Li
,
C. X.
Xu
.
2017
.
Group 2 innate lymphoid cells are involved in skewed type 2 immunity of gastric diseases induced by Helicobacter pylori infection.
Mediators Inflamm.
2017
:
4927964
.
172.
Satoh-Takayama
N.
,
T.
Kato
,
Y.
Motomura
,
T.
Kageyama
,
N.
Taguchi-Atarashi
,
R.
Kinoshita-Daitoku
,
E.
Kuroda
,
J. P.
Di Santo
,
H.
Mimuro
,
K.
Moro
,
H.
Ohno
.
2020
.
Bacteria-induced group 2 innate lymphoid cells in the stomach provide immune protection through induction of IgA.
Immunity
52
:
635
649.e4
.
173.
Kimura
K.
,
T.
Kanai
,
A.
Hayashi
,
Y.
Mikami
,
T.
Sujino
,
S.
Mizuno
,
T.
Handa
,
K.
Matsuoka
,
T.
Hisamatsu
,
T.
Sato
,
T.
Hibi
.
2012
.
Dysregulated balance of retinoid-related orphan receptor γt-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis.
Biochem. Biophys. Res. Commun.
427
:
694
700
.
174.
Takayama
T.
,
N.
Kamada
,
H.
Chinen
,
S.
Okamoto
,
M. T.
Kitazume
,
J.
Chang
,
Y.
Matuzaki
,
S.
Suzuki
,
A.
Sugita
,
K.
Koganei
, et al
2010
.
Imbalance of NKp44+NKp46 and NKp44NKp46+ natural killer cells in the intestinal mucosa of patients with Crohn’s disease.
Gastroenterology
139
:
882
892
.
175.
Geremia
A.
,
C. V.
Arancibia-Cárcamo
,
M. P.
Fleming
,
N.
Rust
,
B.
Singh
,
N. J.
Mortensen
,
S. P.
Travis
,
F.
Powrie
.
2011
.
IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease.
J. Exp. Med.
208
:
1127
1133
.
176.
Mitsialis
V.
,
S.
Wall
,
P.
Liu
,
J.
Ordovas-Montanes
,
T.
Parmet
,
M.
Vukovic
,
D.
Spencer
,
M.
Field
,
C.
McCourt
,
J.
Toothaker
, et al
Boston Children’s Hospital Inflammatory Bowel Disease Center
;
Brigham and Women’s Hospital Crohn’s and Colitis Center
.
2020
.
Single-cell analyses of colon and blood reveal distinct immune cell signatures of ulcerative colitis and Crohn’s disease.
Gastroenterology
159
:
591
608.e10
.
177.
Creyns
B.
,
I.
Jacobs
,
B.
Verstockt
,
J.
Cremer
,
V.
Ballet
,
R.
Vandecasteele
,
T.
Vanuytsel
,
M.
Ferrante
,
S.
Vermeire
,
G.
Van Assche
, et al
2020
.
Biological therapy in inflammatory bowel disease patients partly restores intestinal innate lymphoid cell subtype equilibrium.
Front. Immunol.
11
:
1847
.
178.
Li
J.
,
A. L.
Doty
,
A.
Iqbal
,
S. C.
Glover
.
2016
.
The differential frequency of LineageCRTH2CD45+NKp44CD117CD127+ILC subset in the inflamed terminal ileum of patients with Crohn’s disease.
Cell. Immunol.
304–305
:
63
68
.
179.
Barderas
R.
,
R. A.
Bartolomé
,
M. J.
Fernandez-Aceñero
,
S.
Torres
,
J. I.
Casal
.
2012
.
High expression of IL-13 receptor α2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis.
Cancer Res.
72
:
2780
2790
.
180.
Cella
M.
,
K.
Otero
,
M.
Colonna
.
2010
.
Expansion of human NK-22 cells with IL-7, IL-2, and IL-β reveals intrinsic functional plasticity.
Proc. Natl. Acad. Sci. USA
107
:
10961
10966
.
181.
Lim
A. I.
,
S.
Menegatti
,
J.
Bustamante
,
L.
Le Bourhis
,
M.
Allez
,
L.
Rogge
,
J. L.
Casanova
,
H.
Yssel
,
J. P.
Di Santo
.
2016
.
IL-12 drives functional plasticity of human group 2 innate lymphoid cells.
J. Exp. Med.
213
:
569
583
.
182.
Mazzurana
L.
,
M.
Forkel
,
A.
Rao
,
A.
Van Acker
,
E.
Kokkinou
,
T.
Ichiya
,
S.
Almer
,
C.
Höög
,
D.
Friberg
,
J.
Mjösberg
.
2019
.
Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation.
Eur. J. Immunol.
49
:
1344
1355
.
183.
Silver
J. S.
,
J.
Kearley
,
A. M.
Copenhaver
,
C.
Sanden
,
M.
Mori
,
L.
Yu
,
G. H.
Pritchard
,
A. A.
Berlin
,
C. A.
Hunter
,
R.
Bowler
, et al
2016
.
Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. [Published erratum appears in 2016 Nat. Immunol. 17: 1005.]
Nat. Immunol.
17
:
626
635
.
184.
Cella
M.
,
R.
Gamini
,
C.
Sécca
,
P. L.
Collins
,
S.
Zhao
,
V.
Peng
,
M. L.
Robinette
,
J.
Schettini
,
K.
Zaitsev
,
W.
Gordon
, et al
2019
.
Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues. [Published erratum appears in 2019 Nat. Immunol. 20: 1405.]
Nat. Immunol.
20
:
980
991
.
185.
Li
S.
,
J. J.
Heller
,
J. W.
Bostick
,
A.
Lee
,
H.
Schjerven
,
P.
Kastner
,
S.
Chan
,
Z. E.
Chen
,
L.
Zhou
.
2016
.
Ikaros inhibits group 3 innate lymphoid cell development and function by suppressing the aryl hydrocarbon receptor pathway.
Immunity
45
:
185
197
.
186.
Lim
A. I.
,
Y.
Li
,
S.
Lopez-Lastra
,
R.
Stadhouders
,
F.
Paul
,
A.
Casrouge
,
N.
Serafini
,
A.
Puel
,
J.
Bustamante
,
L.
Surace
, et al
2017
.
Systemic human ILC precursors provide a substrate for tissue ILC differentiation.
Cell
168
:
1086
1100.e10
.
187.
Ciccia
F.
,
A.
Accardo-Palumbo
,
R.
Alessandro
,
A.
Rizzo
,
S.
Principe
,
S.
Peralta
,
F.
Raiata
,
A.
Giardina
,
G.
De Leo
,
G.
Triolo
.
2012
.
Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis.
Arthritis Rheum.
64
:
1869
1878
.
188.
Tugues
S.
,
L.
Ducimetiere
,
E.
Friebel
,
B.
Becher
.
2019
.
Innate lymphoid cells as regulators of the tumor microenvironment.
Semin. Immunol.
41
:
101270
.
189.
Nussbaum
K.
,
S. H.
Burkhard
,
I.
Ohs
,
F.
Mair
,
C. S. N.
Klose
,
S. J.
Arnold
,
A.
Diefenbach
,
S.
Tugues
,
B.
Becher
.
2017
.
Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs.
J. Exp. Med.
214
:
2331
2347
.
190.
Chiossone
L.
,
P. Y.
Dumas
,
M.
Vienne
,
E.
Vivier
.
2018
.
Natural killer cells and other innate lymphoid cells in cancer. [Published erratum appears in 2018 Nat. Immunol. 18: 726.]
Nat. Rev. Immunol.
18
:
671
688
.
191.
Castro
F.
,
A. P.
Cardoso
,
R. M.
Gonçalves
,
K.
Serre
,
M. J.
Oliveira
.
2018
.
Interferon-gamma at the crossroads of tumor immune surveillance or evasion.
Front. Immunol.
9
:
847
.
192.
Wajant
H.
2009
.
The role of TNF in cancer.
Results Probl. Cell Differ.
49
:
1
15
.
193.
Maywald
R. L.
,
S. K.
Doerner
,
L.
Pastorelli
,
C.
De Salvo
,
S. M.
Benton
,
E. P.
Dawson
,
D. G.
Lanza
,
N. A.
Berger
,
S. D.
Markowitz
,
H. J.
Lenz
, et al
2015
.
IL-33 activates tumor stroma to promote intestinal polyposis.
Proc. Natl. Acad. Sci. USA
112
:
E2487
E2496
.
194.
Mertz
K. D.
,
L. F.
Mager
,
M. H.
Wasmer
,
T.
Thiesler
,
V. H.
Koelzer
,
G.
Ruzzante
,
S.
Joller
,
J. R.
Murdoch
,
T.
Brümmendorf
,
V.
Genitsch
, et al
2015
.
The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice.
OncoImmunology
5
:
e1062966
.
195.
O’Donnell
C.
,
A.
Mahmoud
,
J.
Keane
,
C.
Murphy
,
D.
White
,
S.
Carey
,
M.
O’Riordain
,
M. W.
Bennett
,
E.
Brint
,
A.
Houston
.
2016
.
An antitumorigenic role for the IL-33 receptor, ST2L, in colon cancer.
Br. J. Cancer
114
:
37
43
.
196.
Kienzl
M.
,
C.
Hasenoehrl
,
P.
Valadez-Cosmes
,
K.
Maitz
,
A.
Sarsembayeva
,
E.
Sturm
,
A.
Heinemann
,
J.
Kargl
,
R.
Schicho
.
2020
.
IL-33 reduces tumor growth in models of colorectal cancer with the help of eosinophils.
OncoImmunology
9
:
1776059
.
197.
Chevalier
M. F.
,
S.
Trabanelli
,
J.
Racle
,
B.
Salomé
,
V.
Cesson
,
D.
Gharbi
,
P.
Bohner
,
S.
Domingos-Pereira
,
F.
Dartiguenave
,
A. S.
Fritschi
, et al
2017
.
ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence.
J. Clin. Invest.
127
:
2916
2929
.
198.
Trabanelli
S.
,
M. F.
Chevalier
,
A.
Martinez-Usatorre
,
A.
Gomez-Cadena
,
B.
Salomé
,
M.
Lecciso
,
V.
Salvestrini
,
G.
Verdeil
,
J.
Racle
,
C.
Papayannidis
, et al
2017
.
Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.
Nat. Commun.
8
:
593
.
199.
Huang
Q.
,
N.
Jacquelot
,
A.
Preaudet
,
S.
Hediyeh-Zadeh
,
F.
Souza-Fonseca-Guimaraes
,
A. N. J.
McKenzie
,
P. M.
Hansbro
,
M. J.
Davis
,
L. A.
Mielke
,
T. L.
Putoczki
,
G. T.
Belz
.
2021
.
Type 2 innate lymphoid cells protect against colorectal cancer progression and predict improved patient survival.
Cancers (Basel)
13
:
559
.
200.
Wan
J.
,
Y.
Wu
,
L.
Huang
,
Y.
Tian
,
X.
Ji
,
M. H.
Abdelaziz
,
W.
Cai
,
K.
Dineshkumar
,
Y.
Lei
,
S.
Yao
, et al
2021
.
ILC2-derived IL-9 inhibits colorectal cancer progression by activating CD8+ T cells.
Cancer Lett.
502
:
34
43
.
201.
Chan
I. H.
,
R.
Jain
,
M. S.
Tessmer
,
D.
Gorman
,
R.
Mangadu
,
M.
Sathe
,
F.
Vives
,
C.
Moon
,
E.
Penaflor
,
S.
Turner
, et al
2014
.
Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells.
Mucosal Immunol.
7
:
842
856
.
202.
Grivennikov
S. I.
,
K.
Wang
,
D.
Mucida
,
C. A.
Stewart
,
B.
Schnabl
,
D.
Jauch
,
K.
Taniguchi
,
G. Y.
Yu
,
C. H.
Osterreicher
,
K. E.
Hung
, et al
2012
.
Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
Nature
491
:
254
258
.
203.
Kirchberger
S.
,
D. J.
Royston
,
O.
Boulard
,
E.
Thornton
,
F.
Franchini
,
R. L.
Szabady
,
O.
Harrison
,
F.
Powrie
.
2013
.
Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model.
J. Exp. Med.
210
:
917
931
.
204.
Huber
S.
,
N.
Gagliani
,
L. A.
Zenewicz
,
F. J.
Huber
,
L.
Bosurgi
,
B.
Hu
,
M.
Hedl
,
W.
Zhang
,
W.
O’Connor
Jr.
,
A. J.
Murphy
, et al
2012
.
IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.
Nature
491
:
259
263
.
205.
Thompson
C. L.
,
S. J.
Plummer
,
T. C.
Tucker
,
G.
Casey
,
L.
Li
.
2010
.
Interleukin-22 genetic polymorphisms and risk of colon cancer.
Cancer Causes Control
21
:
1165
1170
.
206.
Bergmann
H.
,
S.
Roth
,
K.
Pechloff
,
E. A.
Kiss
,
S.
Kuhn
,
M.
Heikenwälder
,
A.
Diefenbach
,
F. R.
Greten
,
J.
Ruland
.
2017
.
Card9-dependent IL-1β regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer.
Eur. J. Immunol.
47
:
1342
1353
.
207.
Zhu
Y.
,
T.
Shi
,
X.
Lu
,
Z.
Xu
,
J.
Qu
,
Z.
Zhang
,
G.
Shi
,
S.
Shen
,
Y.
Hou
,
Y.
Chen
,
T.
Wang
.
2021
.
Fungal-induced glycolysis in macrophages promotes colon cancer by enhancing innate lymphoid cell secretion of IL-22.
EMBO J.
40
:
e105320
.
208.
Carrega
P.
,
F.
Loiacono
,
E.
Di Carlo
,
A.
Scaramuccia
,
M.
Mora
,
R.
Conte
,
R.
Benelli
,
G. M.
Spaggiari
,
C.
Cantoni
,
S.
Campana
, et al
2015
.
NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures.
Nat. Commun.
6
:
8280
.
209.
Eisenring
M.
,
J.
vom Berg
,
G.
Kristiansen
,
E.
Saller
,
B.
Becher
.
2010
.
IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46.
Nat. Immunol.
11
:
1030
1038
.
210.
Huang
J.
,
H. Y.
Lee
,
X.
Zhao
,
J.
Han
,
Y.
Su
,
Q.
Sun
,
J.
Shao
,
J.
Ge
,
Y.
Zhao
,
X.
Bai
, et al
2021
.
Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93.
Immunity
54
:
673
686.e4
.
211.
Ikeda
A.
,
T.
Ogino
,
H.
Kayama
,
D.
Okuzaki
,
J.
Nishimura
,
S.
Fujino
,
N.
Miyoshi
,
H.
Takahashi
,
M.
Uemura
,
C.
Matsuda
, et al
2020
.
Human NKp44+ group 3 innate lymphoid cells associate with tumor-associated tertiary lymphoid structures in colorectal cancer.
Cancer Immunol. Res.
8
:
724
731
.
212.
Wu
J.
,
H.
Cheng
,
H.
Wang
,
G.
Zang
,
L.
Qi
,
X.
Lv
,
C.
Liu
,
S.
Zhu
,
M.
Zhang
,
J.
Cui
, et al
2021
.
Correlation between immune lymphoid cells and plasmacytoid dendritic cells in human colon cancer.
Front. Immunol.
12
:
601611
.
213.
Nau
D.
,
N.
Altmayer
,
J.
Mattner
.
2014
.
Mechanisms of innate lymphoid cell and natural killer T cell activation during mucosal inflammation.
J. Immunol. Res.
2014
:
546596
.

T.J.W. is the Chief Executive Officer of WebbCures, LLC, cofounded IMMUNE3D and Screen Therapeutics, and is on the scientific advisory board for Immunaccel Labs. C.C. has no financial conflicts of interest.

    Institutional History
  • Associate Professor, University of Maryland, 2009–current

  • Postdoctoral Fellow, Johns Hopkins, 2005–2009

  • Postdoctoral Fellow, Indiana University, 2003–2005

  • Ph.D., Indiana University, 2003

  • B.S., Prairie View A&M University, 1998

    Research Interests
  • Cancer immunology

  • Cancer immunotherapy

  • CD1d-mediated NKT cell activation

  • ELISA and flow cytometry

I am a tenured Associate Professor at the Department of Microbiology and Immunology at the University of Maryland School of Medicine. I earned a B.S. in Biology and Chemistry at Prairie View A&M University and completed my doctoral studies in the Department of Microbiology and Immunology at Indiana University, with studies focused on investigating the role of CD1d1 molecules and NKT cells in antiviral immunity. I conducted postdoctoral fellowships at Indiana University School of Medicine and Johns Hopkins School of Medicine. Studies in my laboratory are focused on investigating factors that impact the development and effector functions of NKT cells. I also contribute significant time to local and national service to increase diversity and equity in academic medicine and healthcare and find time to mentor and share my experiences with STEM scholars and aspiring scientists.

Tonya Webb, Ph.D., Associate Professor

University of Maryland, Baltimore, MD