The complex nature of the innate lymphoid cell (ILC) family and wide range of ILC effector functions has been the focus of intense research. In addition to important roles in host defense, ILCs have central roles in maintaining tissue homeostasis and can promote immune tolerance. Alterations within the microenvironment can impart new functions on ILCs, and can even induce conversion to a distinct ILC family member. Complicating current definitions of ILCs are recent findings of distinct regulatory ILC populations that limit inflammatory responses or recruit other immunosuppressive cells such as regulatory T cells. Whether these populations are distinct ILC family members or rather canonical ILCs that exhibit immunoregulatory functions due to microenvironment signals has been the subject of much debate. In this review, we highlight studies identifying regulatory populations of ILCs that span regulatory NK-like cells, regulatory ILCs, and IL-10–producing ILC2s.

Maintenance of immune tolerance relies on molecular and cellular regulatory mechanisms that keep harmful immune responses in check. Various immune populations that limit innate and adaptive responses to maintain immune homeostasis have been identified. These include the well-studied CD4+ regulatory T cells (Tregs) in addition to noncanonical regulatory B cells, regulatory γδ cells, regulatory CD8+ T cells, regulatory dendritic cells (DCs), regulatory populations of macrophages (commonly referred to as M2 macrophages or alternatively activated macrophages), and, more recently, regulatory populations of innate lymphoid cells (ILCs) (13). These regulatory populations work directly or as part of cellular networks to limit inflammatory immune responses.

Although NK cells have been extensively studied, the discovery that they are part of a family of innate lymphocytes has changed our understanding of how the innate immune system contributes to immunity and tissue homeostasis. Knowledge of ILC diversity and functions is rapidly evolving, but ILCs are currently classified as NK cells, lymphoid tissue inducer cells, group 1 ILCs (ILC1), group 2 ILCs (ILC2), and group 3 ILCs (ILC3) (4, 5). NK cells express T-box transcription factor (TBET) and eomesodermin (EOMES), and produce IFN-γ and TNF-α (5). Similar to NK cells, ILC1s produce IFN-γ and TNF-α but are TBET+EOMESlow/− (5). ILC2s express GATA3 and the retinoic acid (RA) receptor (RAR)–related orphan receptor-α (RORα), and produce IL-4, IL-5, IL-9, and IL-13 (5). ILC3s and lymphoid tissue inducer cells express RORγt and IL-22 or IL-17 alone, or in combination, as well as GM-CSF (5). ILCs lack adaptive Ag-specific receptors but rapidly respond to signals within the microenvironment. Because of overlapping cytokine and transcription factor profiles, ILCs are often considered innate counterparts of effector T cells (5), with noncytotoxic helper ILC subsets (ILC1, ILC2, and ILC3) paralleling the CD4+ Th1, Th2, and Th17 cells, respectively, and NK cells having similar functions to CD8+ cytotoxic T cells (6).

In addition to these well described canonical ILCs, it has been long hypothesized that a regulatory ILC (ILCreg) population exists with analogous functions to CD4+ Tregs. Tregs have essential roles in regulating immunity and maintaining peripheral tolerance (59). Subsets of Tregs include natural CD4+FOXP3+ Tregs, induced CD4+FOXP3+ Tregs, and IL-10–producing type 1 regulatory (Tr1) cells (1, 10). Tregs employ a variety of mechanisms including production of immunosuppressive cytokines TGF-β and IL-10 (11, 12), metabolic disruption via the adenosine pathway (i.e., cAMP, CD39, CD73) (1315), suppression by cytolysis of effector cells (16, 17), and modulation of APCs’ maturation and function (1820). All ILC family members have been associated with negative regulation of immunity in certain contexts, often using similar mechanisms to those used by Tregs including contact-dependent inhibition of T cells, regulation of immune responses through IL-10 or TGF-β, and indirectly via modulation of APCs (2123).

Distinct mechanisms to those employed by Tregs have also been identified. For example, ILC3s express MHC class II (MHC-II) and induce T cell anergy via MHC-II presentation of commensal bacteria Ag in the absence of costimulation (24). ILC2s can express OX40L, which promotes expansion of Th2 cells and Tregs during lung inflammation, displaying a paired role in regulating type-2 immune responses and Tregs (25). ILCs can also indirectly limit inflammation due to effects on other regulatory immune cells. For example, IL-9+ILC2s aided in the resolution of Th17-mediated inflammation in an arthritis model by enhancing suppressive capability of Tregs through ICOSL/ICOS and GITRL/GITR interactions (26) and Zhou et al. reported murine ILC3s secrete IL-2 to maintain survival of Tregs (27). Similarly, IL-33–activated ILC2s enhanced Treg expansion and function in adipose tissue at steady state, whereas IFN-γ from NK cells and ILC1s suppressed ILC2 activation during inflammation or obesity, thereby limiting ILC2-Treg crosstalk and type 2 immune responses (28, 29). Moreover, using a mouse model of allogeneic bone marrow transplant, IL-13+ILC2s increased myeloid derived suppressor cell recruitment to the gastrointestinal tract, which reduced pathogenic donor–derived Th1 and Th17 responses (30). Although best known for killing virally infected or cancerous cells, NK cells have established roles regulating antiviral T cell responses in both mice and humans (reviewed in Refs. 3134). These and many other studies highlight central roles for ILCs in maintaining immune homeostasis.

Although the ability of ILCs to regulate immune responses has been widely observed, recent studies have attempted to identify unique features of ILCreg populations. Yet their existence has been highly controversial, due in part to overlapping properties with other ILC family members, lack of lineage defining transcription factors and limited studies identifying factors that promote ILCreg development or maintain immunoregulatory functions. In light of these observations, the present review focuses on advances of three types of regulatory ILCs: regulatory NK-like cells, ILCregs, and IL-10–producing ILC2s (ILC210). We contrast phenotypic properties and functions with canonical ILC family members, and highlight studies that examine factors governing development and function of ILCreg populations.

Mouse and human NK cells differ in many receptors that regulate their activity and define NK cell subsets. In humans, NK cells are broadly classified as CD56dimCD16+ (CD56dim) NK cells and CD56brightCD16 (CD56bright) NK cells (35). Mice lack the expression of NCAM encoding for CD56, and murine NK cells are typically identified as CD3 NK1.1+CD49b+NKp46+ (36). Mouse CD27+CD11b NK cells are similar in function to CD56bright NK cells, whereas murine CD27CD11b+ NK cell functions overlap with highly cytotoxic CD56dim NK cells (Fig. 1) (37). Cytotoxic CD56dim NK cells, comprising 80–95% of peripheral blood NK cells, kill directly via various mechanisms (Fig. 1) (35, 38, 39). In contrast, circulating CD56bright NK cells are generally associated as more immature NK cells (40, 41). Yet CD56bright NK cells located in secondary lymphoid organs and tissues exhibit a more “regulatory” phenotype, and have sometimes been referred to as “NKregs” (35, 38, 42). Complicating NK cell biology is the tremendous phenotypic heterogeneity exhibited by this ILC family member, with estimates of ∼6,000–30,000 phenotypically distinct circulating NK cells within an individual (43), presenting a challenge in identifying populations with unique functions.

FIGURE 1.

NK cell mechanisms of targeted cell killing. Human NK cells are generally classified as CD56dimCD16+ NK cells and CD56brightCD16 NK cells and mirror mouse NK cell subsets CD27highCD11blow NK cells and CD27lowCD11bhigh NK cells, respectively. Mouse NK cells develop from CD27highCD11blow NK cells, to CD27highCD11bhigh and mature into CD27lowCD11bhigh NK cells. Understanding of human NK cell development is limited, but it is proposed that CD56bright NK cells transition to CD56dimCD16NK cells and CD57 marks terminally differentiated NK cells. Triggering of the Fc receptor CD16 on CD56dim NK cells is central to their functions in mediating Ab dependent cell cytotoxicity (ADCC). Mouse and human NK cells mediate cell killing via stimulatory or lack of inhibitory receptors ligands on target cells, or signaling via the death receptor pathway, TRAIL or CD95L (TRAIL or FasL, respectively). Subsequent NK cell activation causes production of cytotoxic granules, perforin, or granzyme resulting in osmotic lysis or activation of apoptosis in target cells, respectively. NK cells also secrete proinflammatory cytokines, IFN-γ, TNF-α, and GM-CSF.

FIGURE 1.

NK cell mechanisms of targeted cell killing. Human NK cells are generally classified as CD56dimCD16+ NK cells and CD56brightCD16 NK cells and mirror mouse NK cell subsets CD27highCD11blow NK cells and CD27lowCD11bhigh NK cells, respectively. Mouse NK cells develop from CD27highCD11blow NK cells, to CD27highCD11bhigh and mature into CD27lowCD11bhigh NK cells. Understanding of human NK cell development is limited, but it is proposed that CD56bright NK cells transition to CD56dimCD16NK cells and CD57 marks terminally differentiated NK cells. Triggering of the Fc receptor CD16 on CD56dim NK cells is central to their functions in mediating Ab dependent cell cytotoxicity (ADCC). Mouse and human NK cells mediate cell killing via stimulatory or lack of inhibitory receptors ligands on target cells, or signaling via the death receptor pathway, TRAIL or CD95L (TRAIL or FasL, respectively). Subsequent NK cell activation causes production of cytotoxic granules, perforin, or granzyme resulting in osmotic lysis or activation of apoptosis in target cells, respectively. NK cells also secrete proinflammatory cytokines, IFN-γ, TNF-α, and GM-CSF.

Close modal

In addition to central functions in killing virally infected and cancerous cells, NK cells “tune” T cell responses in viral infections, autoimmunity, cancer, and transplantation (reviewed in Refs. 30, 40, and 41) and can regulate B cell responses directly by altering IgG or IgM secretion or indirectly via interactions with CD4+ T follicular helper (Tfh) cells (4446). Regulation of T cells is controlled by germline-encoded activating and inhibitory receptors and coinhibitory or costimulatory molecules that dictate NK cell responsiveness (47). Mechanisms of NK cell regulation include direct killing of T cells, preventing development of central memory T cells, directing cytokine production of CD4+ and CD8+ T cells and preventing CD8+ T cell activation (4856). Recently, NK cell suppression of T cells in LCMV infection was linked to CXCR3 expression that mediated murine NK cell relocalization from red pulp to white pulp or T cell zones of spleen (57). NK cell relocalization DCs by limiting their maturation and stimulatory capabilities or through direct DC killing (5862). Despite the long-standing role for NK cells in regulating immune responses, identifying factors differentiating NK cells with regulatory potential from conventional NK cells engaged in antiviral and antitumor immunity has proven challenging.

A number of studies reported unique cytokine profiles by NK cells that limit T cell responses, yet it is unclear how central these cytokines are to NK cell–mediated regulation. NK cells with nonclassical NK cell cytokine profiles (e.g., IL-10, TGF-β, GM-CSF, IL-22) have been observed and IL-10–producing NK cells have been studied dating back to the 1990s (63). Mehrotra et al. reported CD56+CD16+ NK cells cultured with IL-2 and IL-12 for 24 h expressed IL-10 (63). Separately, an induced IL-10+ NK cell population with reduced IFNG expression that maintained cytotoxic responses to K562 cells was observed (64). Functionally, IL-10+ NK cells suppressed proliferation of Ag-specific CD4+ T cells, and reduced IL-13 and IFN-γ production by T cells (64) (Fig. 2B). Subsequent studies identified mouse IL-10+NK1.1+NKp46+ NK cells with immunoregulatory roles in parasitic, viral, or bacterial infections. For example, treatment with IL-15 complex in experimental cerebral malaria induced IL-10+ NK cells that directly suppressed pathogenic IFN-γ+CD8+ T cells (65) (Fig. 2A). These IL-10+ NK cells were 80% positive for KLRG1 (killer cell lectin-like receptor G1) and CD11b, in line with a memory NK cell phenotype, and maintained expression of IFN-γ in contrast to IFN-γlowIL-10+ NK cells described in humans. In Prf1−/− mice, CMV infection induced IL-10+ NK cells to directly suppress CD8+ T cell responses resulting in viral persistence (51) (Fig. 2A). Mouse IL-10+ NK cells that inhibited DC secretion of IL-12 expanded predominantly in the liver following Toxoplasma gondii infection (66). Expression of IL-10, however, is highly dependent on the type of infection, as local infection with influenza virus in mice did not induce IL-10+ NK cells (66).

FIGURE 2.

Examples of regulatory NK-like cells in mouse and human that display unique cytokines and functions. (A) Examples of regulatory NK-like cells observed in mouse. Mouse CMV infected Prf−/− mice and Plasmodium berghei–infected mice with IL-15 complex (IL-15C) have an expanded IL-10+ NKp46+ regulatory NK-like population that suppresses IFN-γ+CD8+ T cells. Short-term activation with IL-2, IL-12, and IL-15 expands mouse IL-10+TGF-β1+ CTLA-4+ NKp46+ NK cells. (B) Examples of regulatory NK-like cells observed in humans. A distinct CD56+CD3 regulatory NK-like cell in tumor-infiltrating lymphocytes (TILs) of ovarian cancer patients suppresses CD4+ and CD8+ T cell proliferation and IFN-γ production. In vitro stimulation with IL-2 and IL-12 promotes IL-10+ regulatory NK-like cells that suppress Ag-specific CD4+ T cells. An IL-10+TGF-β+CD73+ regulatory NK-like population was identified in sarcoma and breast cancer patients that suppresses CD4+ T cell IFN-γ secretion.

FIGURE 2.

Examples of regulatory NK-like cells in mouse and human that display unique cytokines and functions. (A) Examples of regulatory NK-like cells observed in mouse. Mouse CMV infected Prf−/− mice and Plasmodium berghei–infected mice with IL-15 complex (IL-15C) have an expanded IL-10+ NKp46+ regulatory NK-like population that suppresses IFN-γ+CD8+ T cells. Short-term activation with IL-2, IL-12, and IL-15 expands mouse IL-10+TGF-β1+ CTLA-4+ NKp46+ NK cells. (B) Examples of regulatory NK-like cells observed in humans. A distinct CD56+CD3 regulatory NK-like cell in tumor-infiltrating lymphocytes (TILs) of ovarian cancer patients suppresses CD4+ and CD8+ T cell proliferation and IFN-γ production. In vitro stimulation with IL-2 and IL-12 promotes IL-10+ regulatory NK-like cells that suppress Ag-specific CD4+ T cells. An IL-10+TGF-β+CD73+ regulatory NK-like population was identified in sarcoma and breast cancer patients that suppresses CD4+ T cell IFN-γ secretion.

Close modal

In addition to IL-10, distinct cytokine profiles of “regulatory” NK-like cells have been observed in vitro, during infection, in cancer, and in the semiallogeneic environment of pregnancy (6770). For example, regulatory NK-like cells that suppressed tumor-infiltrating lymphocytes also produced IL-22 and IL-9, with limited IFN-γ and TNF-α production (69). Specialized NK cells termed decidual NK (dNK) cells regulate fetal implantation and protect against maternal rejection of the fetus. These dNK cells comprise up to 70% of lymphocytes in the uterine mucosa and exhibit differential functions and limited cytotoxicity (71). Three distinct dNK cell populations were identified early in the maternal interface that all expressed CD49a (72) and in placental tissue two distinct CD56bright NK cell populations were observed (73). EOMESlowCD49a+ dNK cells exhibited high expression of inhibitor of DNA binding 3 (ID3) (73), a transcriptional regulator that suppresses T cell development and promotes CD56+ cell expansion from human fetal liver cells (74), and in mouse is necessary for TGF-β–induced generation of Tregs (75, 76). Separately, CD56bright dNK cells were found to have low granzyme B, IFN-γ, and TNF-α expression compared with conventional NK cells, and expressed tissue repair factor AREG as well as VEGF (encodes vascular endothelial growth factor), which is important for the migration of trophoblast in late gestation (73). Additionally, GM-CSF expression by dNK cells aids in trophoblast implantation (77), a unique tissue-adapted function. Thus, production of noncanonical cytokines and factors can guide biological processes and NK-like regulatory populations can exhibit tissue-specific functions.

Recent studies have attempted to identify the transcriptional state or surface markers that distinguish regulatory NK-like cells from conventional NK cells. Although numerous studies have demonstrated tumor-infiltrating NK cells commonly have reduced cytotoxic potential and poor cytokine production (reviewed in Ref. 78), regulatory NK-like populations that directly inhibit antitumor T cells have been reported by several groups (reviewed in Refs. 67 and 68). Morandi et al. reported circulating CD56bright NK cells have increased CD73 in comparison with CD56dim NK cells (79). CD73 hydrolyzes AMP to adenosine and is linked to Treg inhibition of DC maturation, polarizing DCs towards a suppressive phenotype, dampening T cell effector functions, and stabilizing Tregs (80). In breast cancer and sarcoma patients high NT5E (CD73) expression was noted and correlated with a worse prognosis (81). This was linked to tumor-infiltrating CD73+ NK cells that upregulated PD-1 and LAG3 after adenosine receptor binding (80, 81). Culture of NK cells from healthy donor blood with sarcoma and breast cancer resections induced CD73+ NK cells that produced IL-10 and TGF-β and inhibited T cell proliferation and IFN-γ expression (81) (Fig. 2B). Inhibiting STAT3 abrogated the ability of CD73+CD56+CD3 NK-like cells to suppress T cells (81); however, blocking CD73 failed to restore T cell proliferation when CD73+ NK cells were present (Fig. 2B) (79). Characterization of CD73+ NK cells demonstrated an ∼8-fold increase in class I–restricted T cell–associated molecule (CRTAM) (81). CRTAM expression by NK cells is tissue specific (i.e., high expression by CD56bright NK cells in healthy human lung) and can differ in disease contexts (82). Although CD56bright NK cells in bone marrow of healthy individuals downregulated CRTAM (82, 83), expansion of a bone marrow CRTAM+CD56+ population that expressed IL-10 and TGF-β and exhibited decreased cytotoxicity with increased PD-1 expression was observed in acute lymphoblastic leukemia patients (84).

We identified a distinct regulatory NK-like population that suppressed CD4+ and CD8+ T cells and correlated with poorer clinical outcomes in ovarian cancer (Fig. 2B) (69). This NK-like ILCreg population displayed unique and overlapping properties with several ILC family members (69). This included expression of KIRs, NKp46, NKG2D/CD94, and CD7 in line with NK cells, but with a unique transcriptional profile, limited IFN-γ, and TNF-α and expression of CCL3, IL-9, and IL-22, associated with ILC1s, ILC2s, and ILC3s, respectively. No difference in FOXP3, IL-10, or TGFB1 expression was observed compared with conventional NK cells but regulatory NK-like cells upregulated ID2, which all ILCs express and is required for mouse NK cell maturation and cytotoxicity (8587). Secreted factors did not appear involved in T cell regulation, but blocking the natural cytotoxicity receptor NKp46 abrogated their ability to suppress T cell proliferation (69).

NKp46, encoded by NCR1, is a conserved marker for NK cells and subsets of ILC3s in both mouse and human, and has also been associated with NK cell regulation of T cell responses (88, 89). Similar to our findings, NKp46 expression by regulatory NK-like cells was also observed in non–small-cell lung carcinoma, where a high proportion of circulating NKp46+CD56dimCD16+ NK cells correlated with worse overall survival (90). These regulatory NKp46+ NK-like cells coexpressed PD-1 and TIM-3, and coculture with tumor-specific T cells suppressed IFN-γ secretion, an effect which was NKp46 dependent (90). Russick et al. characterized a similar NKp46+CTLA-4+ NK cell population in non–small-cell lung carcinoma (91). NKp46+CTLA-4+ NK cells reduced expression of MHC-II and CD86 on CD11c+ DCs, and also correlated with worse overall survival, further supporting regulatory NK-like cells may inhibit antitumor immunity (91).

Mouse viral infection models that support NKp46 is important for NK cell inhibition of antiviral T cells (88, 92). In high dose LCMV infection, NKp46+NK1.1+ NK cells suppressed CD4+ and CD8+ proliferation and limited IFN-γ+ TNF-α+ expression by CD8+ T cells (88, 92). Separately, in vitro stimulation of NK cells with IL-15, IL-18, and IL-12 induced NK cells with an NKp46+CTLA-4+TIM-3+ phenotype that produced TGF-β and IL-10 (89) (Fig. 2A). These studies support regulatory NK-like cells may be identified by NKp46, PD-1, and CTLA-4 expression, but these molecules are also associated with conventional NK cells, limiting their application in differentiating conventional from regulatory NK-like cell populations.

Many questions remain, particularly what factors promote NK-like regulatory cells to be induced and produce noncanonical cytokines such as IL-10, TGF-β, IL-22, or GM-CSF. Are these NK cells that have acquired immunosuppressive functions based on microenvironment signals, or is their development induced from an ILC progenitor population? There are several similarities in phenotypes and mechanisms employed by regulatory-like NK cells and Tregs including IL-10, CTLA-4, PD-1, CD73, and TGF-β. Yet transcriptional networks that drive expression of these molecules have not been defined. Understanding similarities and differences of regulatory NK-like cells from Tregs and conventional NK cells, as well as defining transcription factors which drive suppressive functions or factors that promote regulatory NK-like cell development are needed to bring clarity to disparate observations of regulatory activity in NK cells.

Distinct IL-10–producing ILCregs have been observed by several groups. Kim et al. reported IL-10–producing ILCs marginally increased in a contact hypersensitivity model (93). Following this, an Id3+ ILCreg population was identified that produced IL-10 and TGF-β and limited ILC1s and ILC3s in acute intestinal inflammation (Fig. 3A) (94). ILCregs did not express lineage defining transcription factors or surface markers associated with other ILCs and were defined as CD127+IL-10+TGF-β+ using IL-10–GFP reporter mice (94). Although Id2, which is required for helper ILCs and terminal differentiation of NK cells was necessary for intestinal ILCregs, as the loss of Id3 impaired ILCreg development but not other ILCs (94, 95). TGF-β production sustained ILCregs whereas IL-10 production mediated suppression of ILC1s and ILC3s (94), mirroring Tr1 capacity to limit other CD4+ T helper subsets. Interestingly, in a separate mouse model of colorectal cancer, TGF-β–induced tumor-infiltrating IL-22+ ILC3s to acquire an IL-10+CD127+Id3+ ILCreg phenotype, suggesting that ILCregs may develop from canonical ILCs based on environmental factors (96).

FIGURE 3.

Regulatory helper ILC populations. Populations of ILCregs in mouse (A) and human (B). ILCregs expressing inhibitor of DNA binding 3 (Id3) in mouse and human. Intestinal inflammation and renal ischemia/reperfusion injury were prevented by IL-10+TGF-β1+CD127+ ILCs that suppressed innate populations (ILCs and M1 macrophage) and inflammation, although their existence remains highly controversial. In human tonsil, an ILCFR interacted with germinal center Tfh cells and B cells to suppress IgG, IL-21, and soluble CD40L (sCD40L) secretion. ILC210 in mouse (C) and human (D). In vivo administration of IL-33 in mice, resulted in ILC210 that prevented lung inflammation and islet allograft rejection. In vitro stimuli, IL-2, IL-27, IL-4, and NMU expanded KLRG1+ ILC210. In humans, IL-33 with IL-2 or RA supported expansion of KLRG1+ ILC210.

FIGURE 3.

Regulatory helper ILC populations. Populations of ILCregs in mouse (A) and human (B). ILCregs expressing inhibitor of DNA binding 3 (Id3) in mouse and human. Intestinal inflammation and renal ischemia/reperfusion injury were prevented by IL-10+TGF-β1+CD127+ ILCs that suppressed innate populations (ILCs and M1 macrophage) and inflammation, although their existence remains highly controversial. In human tonsil, an ILCFR interacted with germinal center Tfh cells and B cells to suppress IgG, IL-21, and soluble CD40L (sCD40L) secretion. ILC210 in mouse (C) and human (D). In vivo administration of IL-33 in mice, resulted in ILC210 that prevented lung inflammation and islet allograft rejection. In vitro stimuli, IL-2, IL-27, IL-4, and NMU expanded KLRG1+ ILC210. In humans, IL-33 with IL-2 or RA supported expansion of KLRG1+ ILC210.

Close modal

Supporting potential for ILCregs to impact homeostasis in other tissues, Cao et al. identified a CD127+IL-10+Id3+ ILCreg population in murine kidney that limited ischemia reperfusion injury (Fig. 3A) (97). The frequency of ILCregs was 2.7% of renal ILCs in C57BL/6 mice (97). Adoptive transfer of expanded ILCregs decreased proinflammatory cytokine expression, as well as neutrophil and ILC1 infiltration (97). Human renal nephrectomy samples also contained an ILCreg population (4.3% of ILCs) but rather than being defined by ID3, expression of ILC2 activation markers CD25 and ICOS and the absence of CRTh2 and KLRG1 were used to define human renal ILCregs (97). This study noted IL-2C, a CD25 agonist, induced an ILCreg phenotype in several organs other than the kidney (97), yet the functions were not compared or contrasted across tissues.

Besides confirming ILCs with an ILCreg phenotype are present in human nephrectomy and gut samples, few studies have identified human ID3+ILCreg populations or assessed their functions. O’Connor et al. recently reported a CD127lowCD74+CXCR5+CD7+CCR6+ID3+ follicular ILCreg (ILCFR) in human tonsils with a transcriptional profile similar to Id3+ILCregs (98). TGF-β expression by ILCFR cultured with Tfh cells and B cells from germinal centers reduced IgG secretion, decreased IL-21, and increased soluble CD40L (Fig. 3B) (98). ILCFR transcription factor profile and function were contrasted with ILC3s, and observed ILC3s increased IgG production when cultured with Tfh and B cells contrary to mouse studies that demonstrated MHC-II+ ILC3s interactions with Tfh cells result in reduced colonic IgA (98, 99). These findings and others demonstrate ILCs influence immune responses within lymphoid tissues and control developing immune responses by acting on multiple adaptive immune populations.

Despite intriguing findings on ILCregs, limited studies have identified a distinct ILCreg population, and the role of Id3+ ILCregs in immune responses remains highly controversial. Bando et al. could not replicate findings of Id3+ ILCregs in the intestine using IL-10–eGFP reporter mice bred to C57BL/6J mice (100). IL-10 expressing ILCs in this study did not express the same surface markers and cytokines defined by Wang et al. with less than 1% of LinCD127+GATA3RORγt cells having a phenotype consistent with ILCregs (100). Instead ILC2s were the predominant source of IL-10–producing ILCs in the intestine (100). Lineage tracing studies may yield insights into whether the microenvironment redirects an ILC2 or ILC3 to acquire an ILCreg phenotype and downregulate canonical ILC markers. Yet similar to regulatory NK-like cells, lack of consistent markers and transcription factor expression that differentiates ILCregs from other ILCs presents a challenge.

Landmark studies have demonstrated that natural helper cells, nuocytes, and innate helper 2 cells collectively referred to as ILC2s have the potential to produce IL-10 (101, 102). ILC210s have been referred to as ILC210 or ILC2regs interchangeably. Early reports of helminth expulsion observed ILC2s from spleen produced IL-10 (102), a finding that was also observed in allergic rhinitis (103105). More recently, an ILC210 population was observed in lungs of mice treated with either IL-33 and IL-2 or with chronic exposure to the protease-allergen papain (103). These ILC210s limited lung inflammation and eosinophil recruitment (Fig. 3C) (103). Removal of stimuli resulted in contraction of ILC210, yet these ILCs remained as tissue sentinels, poised to rapidly respond and limit pathogenic inflammatory immune responses (103).

The ILC210s population described by Seehus et al. paralleled a regulatory ILC2 population observed in the lung tissue of house dust mite (HDM)–treated mice and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) that suppressed the proliferation of CD4+ T cells and ILC2s (104). ILC210s were rarely observed in healthy subjects or control-treated mouse lungs, lacked expression of FOXP3, and maintained expression of ILC2-associated transcription factors such as GATA3 (103, 104). In contrast to ILC210 characterized in lung, ILC210 in CRSwNP expressed CTLA-4 and CD25, and downregulated genes encoding ILC2-associated molecules CRTH2, CD127 and CD117 (104).

IL-2, IL-4, IL-27 and soluble neuromedin U (NMU) have been associated with promoting ILC210; however, IL-33 and RA have consistently promoted IL-10–producing ILCs in mouse and human (Fig. 3C, 3D) (100). Seehus et al. demonstrated RA-induced production of IL-10 but not IL-13 in mouse ILC2s (103). Similarly, Morita et al. reported in vitro stimulation with RA-induced IL-10 production by human ILC2s (104). Increased protein expression of retinaldehyde dehydrogenase 1 (RALDH1), an enzyme that converts retinal to RA, was observed in nasal epithelial cells of CRSwNP patients, suggesting epithelial cells synthesize RA during inflammation to promote ILC210 as a means of re-establishing tissue homeostasis (Fig. 3D) (104). RA signals through RAR, which is expressed by all human ILCs (106). IL-10 production was blocked in a dose-dependent manner by addition of a pan-RAR inhibitor to human ILC2s stimulated with IL-2, IL-33, and RA (104). TGF-β in combination with RA inhibited IL-10 production by ILC2s, whereas IL-2 and RA synergized to promote IL-10 production (103). Bando et al. reported IL-2, IL-4, IL-27, and soluble NMU promote IL-10 production by mouse ILC2s, but not by ILC1s, ILC3s, or NK cells, and further showed IL-10 acts in a positive feedback loop to promote additional ILC210 (Fig. 3C) (100). Separately, ILC210 were induced by IL-4 in a murine model of AHR where ILC210 dampened ILC2 effector functions leading to decreased lung inflammation (107). Cytokines and metabolites that promote ILC210 may therefore differ across tissues, highlighting the need to understand how microenvironment signals are integrated to promote ILC210 as part of circuits that maintain tissue homeostasis.

Recent reports of ILC210s have emphasized potential therapeutic applications. In agreement with earlier studies, Golebski et al. confirmed IL-33 and RA induced ILC210 in vitro and reported KLRG1 is required for ILC210s (105). Single-cell analysis of ILC210 demonstrated increased expression of genes implicated in the retinol metabolism pathway including RARA and RARG (105). IL-10+KLRG1+ ILC2s decreased activation of naive CD4+ T cells, limited Th1 and Th17 cell responses, and maintained epithelial cell integrity (105). In addition, the authors observed patients with grass pollen allergy had lower levels of IL-10+KLRG1+ ILC2s compared with healthy controls (105). In a double-blind, placebo-controlled clinical trial, ILC210 were restored following grass pollen allergen-specific immunotherapy (AIT). Separately, IL-10+CTLA-4+ ILCs increased by 3.2% after 2 y in HDM allergic rhinitis receiving AIT (108). Together, the frequency of ILC210 increases in response to AIT for allergic responses, and approaches which promote their activity may have therapeutic applications in allergic airway inflammation.

The immunoregulatory potential of ILC210 was also highlighted in mouse islet allograft and traumatic brain injury models (109, 110). In vivo IL-33 administration to mice receiving allogenic islets resulted in expansion of ILC2s and Tregs, and enhanced islet allograft survival (109). Two subtypes of ILC2s were identified within the islet allograft: ILC210s and non–ILC210s (109). Adoptive transfer of ILC210 prolonged islet allograft survival, supporting the therapeutic potential of harnessing ILC210 in islet transplantation (Fig. 3C) (109). Separately, AMP-activated protein kinase (AMPK) was linked to ILC210 in a mouse model of traumatic brain injury (110). Inhibition of AMPK increased all ILC subsets within the meninges, whereas AMPK activation selectively increased numbers of ILC210 at the expense of ILC1s and ILC3s (110). Use of AMPK activator metformin led to expansion of ILC210 and a corresponding decrease in ILC1s and ILC3s, demonstrating potential of AMPK-activating therapeutics to enhance ILC210 expansion (110).

It is unknown whether specific transcription factors are required for ILC210 activity. ILC210 do not express FOXP3 and few studies have identified gene expression patterns that direct the divergence of ILC2s to ILC210. Howard et al. demonstrated IL-4–mediated induction of mouse ILC210 via an IL-4–STAT6 axis corresponded with upregulation of c-musculoaponeurotic fibrosarcoma (cMaf) and B lymphocyte-induced maturation protein-1 (Blimp-1) (107). Knockdown of cMaf or Blimp-1 prevented IL-10 production by ILC210 (107), in line with established roles for cMaf and Blimp-1 in regulating IL-10 (111–114) and paralleling Tr1 cells that are Blimp-1 dependent (115). Yet, BLIMP1 was not differentially expressed in KLRG1+ ILC210 in individuals with grass pollen allergic rhinitis, nor was HELIOS and IRF4 (105). Morita et al. detected upregulation of HELIOS in IL-10+ ILC2s, but confirmed no difference at the protein level (104). In lung ILC210 of IL-33–treated mice, higher expression of forkhead box F1 (Foxf1), activating transcription factor 3 (Atf3), Klf2 (Krüppel-like factor 2) and Id3 was observed compared with IL-10 ILC2s, indicating potential roles in ILC210 development or function (103). Although the function of Foxf1 and Atf3 in ILCs have not been reported, KLF2 regulates NK cell proliferation and survival and Id3 was also observed in ILCregs and NK-like regulatory cells (73, 95, 103). However, Id3 was not differentially expressed in ILC210 in HDM-treated mice or in vitro–expanded human ILC210, indicating Id3 is not required for ILC210 function. Elucidating the transcription factor network that directs the development or function of regulatory ILC210 will be important moving forward to delineate the role of ILC210 in maintaining immune homeostasis.

ILCs are often considered the innate counterpart of T cells due to overlapping transcription factor and cytokine expression profiles. Yet a developmentally distinct ILCreg subset central to immune tolerance similar to natural CD4+FOXP3+ Tregs has not been established. Questions remain as to whether any of these ILCreg subsets can be considered distinct from canonical ILCs, or if instead ILCreg populations acquire immunosuppressive functions from microenvironment signals. ILCs display a high degree of plasticity, acquiring new phenotypes and functions based on factors within the tissue niche. Evidence to date mostly supports conversion of canonical ILC subsets to ILCreg populations. Indeed, in many ways ILCs are similar to macrophages, existing on a spectrum of phenotypes and functions. Of note, Id2 is important for both ILC and myeloid lineage development, including monocyte to macrophage differentiation (116, 117) and blocks T cell development (118, 119). ILC2s could potentially mirror alternatively activated/M2-like macrophages, which can express IL-10 and develop downstream of cytokines including IL-4 and IL-13 (120, 121). The paradigm of ILCs mirroring T cell subsets may not accurately reflect tissue-adapted functions of ILCs in all cases, and perhaps looking to myeloid studies may provide new insights into ILC development and function.

Overlapping phenotypic properties and IL-10 production by ILCregs and ILC210 make distinguishing these two ILCreg populations challenging. Of note, ILC210 downregulated CRTH2 and other canonical ILC2 markers (104), and Id3 expression has been reported in both populations. More research is needed to confirm whether the ILCregs and ILC210 are distinct or rather the same population with slightly altered phenotypic profiles based on the tissue or model employed. Similar to studies of regulatory NK-like populations, lack of specific markers or transcription factors that distinguish inflammatory from regulatory populations creates a challenge for interpreting findings.

Beyond gaps in understanding development of ILCreg populations, the stability of regulatory NK-like cells, ILCregs, and ILC210 is unclear. Whether removal of stimuli results in regulatory populations reverting back to canonical ILCs has not been determined. Further investigation is needed to assess epigenetic regulation of transcription factor and cytokine loci. With the advancement of single-cell RNA sequencing and proteomic approaches, addressing ILCreg stability within the context of heterogenous ILC populations in health and disease is now possible. Determining the stability or plasticity of ILCreg populations will enhance our understanding of immune tolerance mechanisms and inform if harnessing or inhibiting ILCreg populations may have applications in new therapeutic approaches.

We thank Sarah J. Colpitts for careful reading of the manuscript. Figures were created with BioRender.com.

This work was supported by funding from the Canadian Institutes for Health Research (168960 and 169084) and a Natural Sciences and Engineering Research Council of Canada Discovery Grant to S.Q.C.’s research program.

Abbreviations used in this article

AIT

allergen-specific immunotherapy

AMPK

AMP-activated protein kinase

CRSwNP

chronic rhinosinusitis with nasal polyps

CRTAM

class I–restricted T cell–associated molecule

DC

dendritic cell

dNK

decidual NK cell

EOMES

eomesodermin

HDM

house dust mite

ILC

innate lymphoid cell

ILC1

group 1 ILC

ILC2

group 2 ILC

ILC210

IL-10–producing ILC2

ILC3

group 3 ILC

ILCFR

follicular regulatory innate lymphoid cell

ILCreg

regulatory ILC

MHC-II

MHC class II

NMU

neuromedin U

RA

retinoic acid

RAR

RA receptor

Tfh

T follicular helper

Tr1

type 1 regulatory cell

Treg

regulatory T cell

1.
Zhao
H.
,
R.
Feng
,
A.
Peng
,
G.
Li
,
L.
Zhou
.
2019
.
The expanding family of noncanonical regulatory cell subsets.
J. Leukoc. Biol.
106
:
369
383
.
2.
Wang
L.-X.
,
S.-X.
Zhang
,
H.-J.
Wu
,
X.-L.
Rong
,
J.
Guo
.
2018
.
M2b macrophage polarization and its roles in diseases.
J. Leukoc. Biol.
106
:
345
358
.
3.
Mantovani
A.
,
A.
Sica
,
S.
Sozzani
,
P.
Allavena
,
A.
Vecchi
,
M.
Locati
.
2004
.
The chemokine system in diverse forms of macrophage activation and polarization.
Trends Immunol.
25
:
677
686
.
4.
Eberl
G.
,
M.
Colonna
,
J. P.
Di Santo
,
A. N. J.
McKenzie
.
2015
.
Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.
Science
348
:
aaa6566
.
5.
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
.
6.
Spits
H.
,
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
2013
.
Innate lymphoid cells--a proposal for uniform nomenclature.
Nat. Rev. Immunol.
13
:
145
149
.
7.
Sakaguchi
S.
,
N.
Sakaguchi
,
M.
Asano
,
M.
Itoh
,
M.
Toda
.
1995
.
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
J. Immunol.
155
:
1151
1164
.
8.
Sakaguchi
S.
,
T.
Yamaguchi
,
T.
Nomura
,
M.
Ono
.
2008
.
Regulatory T cells and immune tolerance.
Cell
133
:
775
787
.
9.
Sakaguchi
S.
,
N.
Mikami
,
J. B.
Wing
,
A.
Tanaka
,
K.
Ichiyama
,
N.
Ohkura
.
2020
.
Regulatory T cells and human disease.
Annu. Rev. Immunol.
38
:
541
566
.
10.
Fontenot
J. D.
,
M. A.
Gavin
,
A. Y.
Rudensky
.
2003
.
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
Nat. Immunol.
4
:
330
336
.
11.
Taylor
A.
,
J.
Verhagen
,
K.
Blaser
,
M.
Akdis
,
C. A.
Akdis
.
2006
.
Mechanisms of immune suppression by interleukin-10 and transforming growth factor-β: the role of T regulatory cells.
Immunology
117
:
433
442
.
12.
Letterio
J. J.
,
A. B.
Roberts
.
1998
.
Regulation of immune responses by TGF-beta.
Annu. Rev. Immunol.
16
:
137
161
.
13.
Borsellino
G.
,
M.
Kleinewietfeld
,
D.
Di Mitri
,
A.
Sternjak
,
A.
Diamantini
,
R.
Giometto
,
S.
Höpner
,
D.
Centonze
,
G.
Bernardi
,
M. L.
Dell’Acqua
, et al
2007
.
Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.
Blood
110
:
1225
1232
.
14.
Deaglio
S.
,
K. M.
Dwyer
,
W.
Gao
,
D.
Friedman
,
A.
Usheva
,
A.
Erat
,
J.-F.
Chen
,
K.
Enjyoji
,
J.
Linden
,
M.
Oukka
, et al
2007
.
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.
J. Exp. Med.
204
:
1257
1265
.
15.
Whiteside
T. L.
,
M.
Mandapathil
,
P.
Schuler
.
2011
.
The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg).
Curr. Med. Chem.
18
:
5217
5223
.
16.
Gondek
D. C.
,
L.-F.
Lu
,
S. A.
Quezada
,
S.
Sakaguchi
,
R. J.
Noelle
.
2005
.
Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism.
J. Immunol.
174
:
1783
1786
.
17.
Cao
X.
,
S. F.
Cai
,
T. A.
Fehniger
,
J.
Song
,
L. I.
Collins
,
D. R.
Piwnica-Worms
,
T. J.
Ley
.
2007
.
Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance.
Immunity
27
:
635
646
.
18.
Read
S.
,
V.
Malmström
,
F.
Powrie
.
2000
.
Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.
J. Exp. Med.
192
:
295
302
.
19.
Huang
C.-T.
,
C. J.
Workman
,
D.
Flies
,
X.
Pan
,
A. L.
Marson
,
G.
Zhou
,
E. L.
Hipkiss
,
S.
Ravi
,
J.
Kowalski
,
H. I.
Levitsky
, et al
2004
.
Role of LAG-3 in regulatory T cells.
Immunity
21
:
503
513
.
20.
Park
H. J.
,
J. S.
Park
,
Y. H.
Jeong
,
J.
Son
,
Y. H.
Ban
,
B.-H.
Lee
,
L.
Chen
,
J.
Chang
,
D. H.
Chung
,
I.
Choi
,
S.-J.
Ha
.
2015
.
PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells.
J. Immunol.
194
:
5801
5811
.
21.
Withers
D. R.
,
M. R.
Hepworth
.
2017
.
Group 3 innate lymphoid cells: communications hubs of the intestinal immune system.
Front. Immunol.
8
:
1298
.
22.
Klose
C. S. N.
,
D.
Artis
.
2016
.
Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis.
Nat. Immunol.
17
:
765
774
.
23.
Withers
D. R
.
2016
.
Innate lymphoid cell regulation of adaptive immunity.
Immunology
149
:
123
130
.
24.
Hepworth
M. R.
,
T. C.
Fung
,
S. H.
Masur
,
J. R.
Kelsen
,
F. M.
McConnell
,
J.
Dubrot
,
D. R.
Withers
,
S.
Hugues
,
M. A.
Farrar
,
W.
Reith
, et al
2015
.
Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells.
Science
348
:
1031
1035
.
25.
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
.
26.
Rauber
S.
,
M.
Luber
,
S.
Weber
,
L.
Maul
,
A.
Soare
,
T.
Wohlfahrt
,
N.-Y.
Lin
,
K.
Dietel
,
A.
Bozec
,
M.
Herrmann
, et al
2017
.
Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells.
Nat. Med.
23
:
938
944
.
27.
Zhou
L.
,
C.
Chu
,
F.
Teng
,
N. J.
Bessman
,
J.
Goc
,
E. K.
Santosa
,
G. G.
Putzel
,
H.
Kabata
,
J. R.
Kelsen
,
R. N.
Baldassano
, et al
2019
.
Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2.
Nature
568
:
405
409
.
28.
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
.
29.
Sasaki
T.
,
K.
Moro
,
T.
Kubota
,
N.
Kubota
,
T.
Kato
,
H.
Ohno
,
S.
Nakae
,
H.
Saito
,
S.
Koyasu
.
2019
.
Innate lymphoid cells in the induction of obesity.
Cell Rep.
28
:
202
217.e7
.
30.
Bruce
D. W.
,
H. E.
Stefanski
,
B. G.
Vincent
,
T. A.
Dant
,
S.
Reisdorf
,
H.
Bommiasamy
,
D. A.
Serody
,
J. E.
Wilson
,
K. P.
McKinnon
,
W. D.
Shlomchik
, et al
2017
.
Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease.
J. Clin. Invest.
127
:
1813
1825
.
31.
Cook
K. D.
,
S. N.
Waggoner
,
J. K.
Whitmire
.
2014
.
NK cells and their ability to modulate T cells during virus infections.
Crit. Rev. Immunol.
34
:
359
388
.
32.
Schuster
I. S.
,
J. D.
Coudert
,
C. E.
Andoniou
,
M. A.
Degli-Esposti
.
2016
.
“Natural regulators”: NK cells as modulators of T cell immunity.
Front. Immunol.
7
:
235
.
33.
Waggoner
S. N.
,
S. D.
Reighard
,
I. E.
Gyurova
,
S. A.
Cranert
,
S. E.
Mahl
,
E. P.
Karmele
,
J. P.
McNally
,
M. T.
Moran
,
T. R.
Brooks
,
F.
Yaqoob
,
C. E.
Rydyznski
.
2016
.
Roles of natural killer cells in antiviral immunity.
Curr. Opin. Virol.
16
:
15
23
.
34.
Zwirner
N. W.
,
C. I.
Domaica
,
M. B.
Fuertes
.
2020
.
Regulatory functions of NK cells during infections and cancer.
J. Leukoc. Biol.
109
:
185
194
.
35.
Poli
A.
,
T.
Michel
,
M.
Thérésine
,
E.
Andrès
,
F.
Hentges
,
J.
Zimmer
.
2009
.
CD56bright natural killer (NK) cells: an important NK cell subset.
Immunology
126
:
458
465
.
36.
Goh
W.
,
N. D.
Huntington
.
2017
.
Regulation of murine natural killer cell development.
Front. Immunol.
8
:
130
.
37.
Hayakawa
Y.
,
M. J.
Smyth
.
2006
.
CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity.
J. Immunol.
176
:
1517
1524
.
38.
Wu
Y.
,
Z.
Tian
,
H.
Wei
.
2017
.
Developmental and functional control of natural killer cells by cytokines.
Front. Immunol.
8
:
930
.
39.
Collins
P. L.
,
M.
Cella
,
S. I.
Porter
,
S.
Li
,
G. L.
Gurewitz
,
H. S.
Hong
,
R. P.
Johnson
,
E. M.
Oltz
,
M.
Colonna
.
2019
.
Gene regulatory programs conferring phenotypic identities to human NK cells.
Cell
176
:
348
360.e12
.
40.
Cooley
S.
,
F.
Xiao
,
M.
Pitt
,
M.
Gleason
,
V.
McCullar
,
T. L.
Bergemann
,
K. L.
McQueen
,
L. A.
Guethlein
,
P.
Parham
,
J. S.
Miller
.
2007
.
A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature.
Blood
110
:
578
586
.
41.
Nagler
A.
,
L. L.
Lanier
,
S.
Cwirla
,
J. H.
Phillips
.
1989
.
Comparative studies of human FcRIII-positive and negative natural killer cells.
J. Immunol.
143
:
3183
3191
.
42.
Michel
T.
,
A.
Poli
,
A.
Cuapio
,
B.
Briquemont
,
G.
Iserentant
,
M.
Ollert
,
J.
Zimmer
.
2016
.
Human CD56 bright NK cells: an update.
J. Immunol.
196
:
2923
2931
.
43.
Horowitz
A.
,
D. M.
Strauss-Albee
,
M.
Leipold
,
J.
Kubo
,
N.
Nemat-Gorgani
,
O. C.
Dogan
,
C. L.
Dekker
,
S.
Mackey
,
H.
Maecker
,
G. E.
Swan
, et al
2013
.
Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry.
Sci. Transl. Med.
5
:
208ra145
.
44.
Pierce
S.
,
E. S.
Geanes
,
T.
Bradley
.
2020
.
Targeting natural killer cells for improved immunity and control of the adaptive immune response.
Front. Cell. Infect. Microbiol.
10
:
231
.
45.
Cook
K. D.
,
H. C.
Kline
,
J. K.
Whitmire
.
2015
.
NK cells inhibit humoral immunity by reducing the abundance of CD4+ T follicular helper cells during a chronic virus infection.
J. Leukoc. Biol.
98
:
153
162
.
46.
Rydyznski
C.
,
K. A.
Daniels
,
E. P.
Karmele
,
T. R.
Brooks
,
S. E.
Mahl
,
M. T.
Moran
,
C.
Li
,
R.
Sutiwisesak
,
R. M.
Welsh
,
S. N.
Waggoner
.
2015
.
Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells.
Nat. Commun.
6
:
6375
.
47.
Ljunggren
H. G.
,
K.
Kärre
.
1990
.
In search of the ‘missing self’: MHC molecules and NK cell recognition.
Immunol. Today
11
:
237
244
.
48.
Martín-Fontecha
A.
,
L. L.
Thomsen
,
S.
Brett
,
C.
Gerard
,
M.
Lipp
,
A.
Lanzavecchia
,
F.
Sallusto
.
2004
.
Induced recruitment of NK cells to lymph nodes provides IFN-γ for T(H)1 priming.
Nat. Immunol.
5
:
1260
1265
.
49.
Morandi
B.
,
G.
Bougras
,
W. A.
Muller
,
G.
Ferlazzo
,
C.
Münz
.
2006
.
NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-γ secretion.
Eur. J. Immunol.
36
:
2394
2400
.
50.
Laouar
Y.
,
F. S.
Sutterwala
,
L.
Gorelik
,
R. A.
Flavell
.
2005
.
Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ.
Nat. Immunol.
6
:
600
607
.
51.
Lee
S. H.
,
K. S.
Kim
,
N.
Fodil-Cornu
,
S. M.
Vidal
,
C. A.
Biron
.
2009
.
Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection.
J. Exp. Med.
206
:
2235
2251
.
52.
Soderquest
K.
,
T.
Walzer
,
B.
Zafirova
,
L. S.
Klavinskis
,
B.
Polić
,
E.
Vivier
,
G. M.
Lord
,
A.
Martín-Fontecha
.
2011
.
Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses.
J. Immunol.
186
:
3304
3308
.
53.
Rabinovich
B. A.
,
J.
Li
,
J.
Shannon
,
R.
Hurren
,
J.
Chalupny
,
D.
Cosman
,
R. G.
Miller
.
2003
.
Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells.
J. Immunol.
170
:
3572
3576
.
54.
Cerboni
C.
,
A.
Zingoni
,
M.
Cippitelli
,
M.
Piccoli
,
L.
Frati
,
A.
Santoni
.
2007
.
Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis.
Blood
110
:
606
615
.
55.
Lu
L.
,
K.
Ikizawa
,
D.
Hu
,
M. B. F.
Werneck
,
K. W.
Wucherpfennig
,
H.
Cantor
.
2007
.
Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway.
Immunity
26
:
593
604
.
56.
Waggoner
S. N.
,
R. T.
Taniguchi
,
P. A.
Mathew
,
V.
Kumar
,
R. M.
Welsh
.
2010
.
Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis.
J. Clin. Invest.
120
:
1925
1938
.
57.
Ali
A.
,
L. M.
Canaday
,
H. A.
Feldman
,
H.
Cevik
,
M. T.
Moran
,
S.
Rajaram
,
N.
Lakes
,
J. A.
Tuazon
,
H.
Seelamneni
,
D.
Krishnamurthy
, et al
2021
.
Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues.
J. Clin. Invest.
DOI: 10.1172/JCI146686.
58.
Gerosa
F.
,
B.
Baldani-Guerra
,
C.
Nisii
,
V.
Marchesini
,
G.
Carra
,
G.
Trinchieri
.
2002
.
Reciprocal activating interaction between natural killer cells and dendritic cells.
J. Exp. Med.
195
:
327
333
.
59.
Mocikat
R.
,
H.
Braumüller
,
A.
Gumy
,
O.
Egeter
,
H.
Ziegler
,
U.
Reusch
,
A.
Bubeck
,
J.
Louis
,
R.
Mailhammer
,
G.
Riethmüller
, et al
2003
.
Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses.
Immunity
19
:
561
569
.
60.
Cook
K. D.
,
J. K.
Whitmire
.
2012
.
The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection.
J. Immunol.
190
:
641
649
.
61.
Andrews
D. M.
,
M. J.
Estcourt
,
C. E.
Andoniou
,
M. E.
Wikstrom
,
A.
Khong
,
V.
Voigt
,
P.
Fleming
,
H.
Tabarias
,
G. R.
Hill
,
R. G.
van der Most
, et al
2010
.
Innate immunity defines the capacity of antiviral T cells to limit persistent infection.
J. Exp. Med.
207
:
1333
1343
.
62.
Hayakawa
Y.
,
V.
Screpanti
,
H.
Yagita
,
A.
Grandien
,
H.-G.
Ljunggren
,
M. J.
Smyth
,
B. J.
Chambers
.
2004
.
NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy.
J. Immunol.
172
:
123
129
.
63.
Mehrotra
P. T.
,
R. P.
Donnelly
,
S.
Wong
,
H.
Kanegane
,
A.
Geremew
,
H. S.
Mostowski
,
K.
Furuke
,
J. P.
Siegel
,
E. T.
Bloom
.
1998
.
Production of IL-10 by human natural killer cells stimulated with IL-2 and/or IL-12.
J. Immunol.
160
:
2637
2644
.
64.
Deniz
G.
,
G.
Erten
,
U. C.
Kücüksezer
,
D.
Kocacik
,
C.
Karagiannidis
,
E.
Aktas
,
C. A.
Akdis
,
M.
Akdis
.
2008
.
Regulatory NK cells suppress antigen-specific T cell responses.
J. Immunol.
180
:
850
857
.
65.
Burrack
K. S.
,
M. A.
Huggins
,
E.
Taras
,
P.
Dougherty
,
C. M.
Henzler
,
R.
Yang
,
S.
Alter
,
E. K.
Jeng
,
H. C.
Wong
,
M.
Felices
, et al
2018
.
Interleukin-15 complex treatment protects mice from cerebral malaria by inducing interleukin-10-producing natural killer cells.
Immunity
48
:
760
772.e4
.
66.
Perona-Wright
G.
,
K.
Mohrs
,
F. M.
Szaba
,
L. W.
Kummer
,
R.
Madan
,
C. L.
Karp
,
L. L.
Johnson
,
S. T.
Smiley
,
M.
Mohrs
.
2009
.
Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells.
Cell Host Microbe
6
:
503
512
.
67.
Crouse
J.
,
H. C.
Xu
,
P. A.
Lang
,
A.
Oxenius
.
2015
.
NK cells regulating T cell responses: mechanisms and outcome.
Trends Immunol.
36
:
49
58
.
68.
Crome
S. Q.
,
P. A.
Lang
,
K. S.
Lang
,
P. S.
Ohashi
.
2013
.
Natural killer cells regulate diverse T cell responses.
Trends Immunol.
34
:
342
349
.
69.
Crome
S. Q.
,
L. T.
Nguyen
,
S.
Lopez-Verges
,
S. Y. C.
Yang
,
B.
Martin
,
J. Y.
Yam
,
D. J.
Johnson
,
J.
Nie
,
M.
Pniak
,
P. H.
Yen
, et al
2017
.
A distinct innate lymphoid cell population regulates tumor-associated T cells.
Nat. Med.
23
:
368
375
.
70.
Sojka
D. K.
,
L.
Yang
,
W. M.
Yokoyama
.
2019
.
Uterine natural killer cells.
Front. Immunol.
10
:
960
.
71.
Erlebacher
A
.
2014
.
19 - Leukocyte population dynamics and functions at the maternal–fetal interface.
In
The Guide to Investigation of Mouse Pregnancy.
B. A.
Croy
,
A. T.
Yamada
,
F. J.
DeMayo
,
S. L.
Adamson
.
Academic Press
,
Boston
, p.
227
242
.
72.
Vento-Tormo
R.
,
M.
Efremova
,
R. A.
Botting
,
M. Y.
Turco
,
M.
Vento-Tormo
,
K. B.
Meyer
,
J.-E.
Park
,
E.
Stephenson
,
K.
Polański
,
A.
Goncalves
, et al
2018
.
Single-cell reconstruction of the early maternal-fetal interface in humans.
Nature
563
:
347
353
.
73.
Vazquez
J.
,
D. A.
Chasman
,
G. E.
Lopez
,
C. T.
Tyler
,
I. M.
Ong
,
A. K.
Stanic
.
2020
.
Transcriptional and functional programming of decidual innate lymphoid cells.
Front. Immunol.
10
:
3065
.
74.
Heemskerk
M. H. M.
,
B.
Blom
,
G.
Nolan
,
A. P. A.
Stegmann
,
A. Q.
Bakker
,
K.
Weijer
,
P. C. M.
Res
,
H.
Spits
.
1997
.
Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3.
J. Exp. Med.
186
:
1597
1602
.
75.
Maruyama
T.
,
J.
Li
,
J. P.
Vaque
,
J. E.
Konkel
,
W.
Wang
,
B.
Zhang
,
P.
Zhang
,
B. F.
Zamarron
,
D.
Yu
,
Y.
Wu
, et al
2010
.
Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3.
Nat. Immunol.
12
:
86
95
.
76.
Rauch
K. S.
,
M.
Hils
,
E.
Lupar
,
S.
Minguet
,
M.
Sigvardsson
,
M. E.
Rottenberg
,
A.
Izcue
,
C.
Schachtrup
,
K.
Schachtrup
.
2016
.
Id3 maintains Foxp3 expression in regulatory T cells by controlling a transcriptional network of E47, Spi-B, and SOCS3.
Cell Rep.
17
:
2827
2836
.
77.
Xiong
S.
,
A. M.
Sharkey
,
P. R.
Kennedy
,
L.
Gardner
,
L. E.
Farrell
,
O.
Chazara
,
J.
Bauer
,
S. E.
Hiby
,
F.
Colucci
,
A.
Moffett
.
2013
.
Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation.
J. Clin. Invest.
123
:
4264
4272
.
78.
Cózar
B.
,
M.
Greppi
,
S.
Carpentier
,
E.
Narni-Mancinelli
,
L.
Chiossone
,
E.
Vivier
.
2020
.
Tumor-infiltrating natural killer cells.
Cancer Discov.
11
:
34
44
.
79.
Morandi
F.
,
A. L.
Horenstein
,
A.
Chillemi
,
V.
Quarona
,
S.
Chiesa
,
A.
Imperatori
,
S.
Zanellato
,
L.
Mortara
,
M.
Gattorno
,
V.
Pistoia
,
F.
Malavasi
.
2015
.
CD56bright CD16− NK cells produce adenosine through a CD38-mediated pathway and act as regulatory cells inhibiting autologous CD4+ T cell proliferation.
J. Immunol.
195
:
965
972
.
80.
Leone
R. D.
,
L. A.
Emens
.
2018
.
Targeting adenosine for cancer immunotherapy.
J. Immunother. Cancer
6
:
57
.
81.
Neo
S. Y.
,
Y.
Yang
,
J.
Record
,
R.
Ma
,
X.
Chen
,
Z.
Chen
,
N. P.
Tobin
,
E.
Blake
,
C.
Seitz
,
R.
Thomas
, et al
2020
.
CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment.
J. Clin. Invest.
130
:
1185
1198
.
82.
Dogra
P.
,
C.
Rancan
,
W.
Ma
,
M.
Toth
,
T.
Senda
,
D. J.
Carpenter
,
M.
Kubota
,
R.
Matsumoto
,
P.
Thapa
,
P. A.
Szabo
, et al
2020
.
Tissue determinants of human NK cell development, function, and residence.
Cell
180
:
749
763.e13
.
83.
Koues
O. I.
,
P. L.
Collins
,
M.
Cella
,
M. L.
Robinette
,
S. I.
Porter
,
S. C.
Pyfrom
,
J. E.
Payton
,
M.
Colonna
,
E. M.
Oltz
.
2016
.
Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells.
Cell
165
:
1134
1146
.
84.
Ramírez-Ramírez
D.
,
S.
Padilla-Castañeda
,
C. S.
Galán-Enríquez
,
E.
Vadillo
,
J. L.
Prieto-Chávez
,
E.
Jiménez-Hernández
,
A.
Vilchis-Ordóñez
,
A.
Sandoval
,
J. C.
Balandrán
,
S. M.
Pérez-Tapia
, et al
2019
.
CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow.
J. Leukoc. Biol.
105
:
999
1013
.
85.
Carotta
S.
,
S. H. M.
Pang
,
S. L.
Nutt
,
G. T.
Belz
.
2011
.
Identification of the earliest NK-cell precursor in the mouse BM.
Blood
117
:
5449
5452
.
86.
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
.
87.
Yokota
Y.
,
A.
Mansouri
,
S.
Mori
,
S.
Sugawara
,
S.
Adachi
,
S.
Nishikawa
,
P.
Gruss
.
1999
.
Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2.
Nature
397
:
702
706
.
88.
Pallmer
K.
,
I.
Barnstorf
,
N. S.
Baumann
,
M.
Borsa
,
S.
Jonjic
,
A.
Oxenius
.
2019
.
NK cells negatively regulate CD8 T cells via natural cytotoxicity receptor (NCR) 1 during LCMV infection.
PLoS Pathog.
15
:
e1007725
.
89.
Oka
N.
,
T.
Markova
,
K.
Tsuzuki
,
W.
Li
,
Y.
El-Darawish
,
M.
Pencheva-Demireva
,
K.
Yamanishi
,
H.
Yamanishi
,
M.
Sakagami
,
Y.
Tanaka
,
H.
Okamura
.
2020
.
IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18.
Cancer Immunol. Immunother.
69
:
1699
1712
.
90.
Picard
E.
,
Y.
Godet
,
C.
Laheurte
,
M.
Dosset
,
J.
Galaine
,
L.
Beziaud
,
R.
Loyon
,
L.
Boullerot
,
E.
Lauret Marie Joseph
,
L.
Spehner
, et al
2018
.
Circulating NKp46+ natural killer cells have a potential regulatory property and predict distinct survival in non-small cell lung cancer.
OncoImmunology
8
:
e1527498
.
91.
Russick
J.
,
P.-E.
Joubert
,
M.
Gillard-Bocquet
,
C.
Torset
,
M.
Meylan
,
F.
Petitprez
,
M.-A.
Dragon-Durey
,
S.
Marmier
,
A.
Varthaman
,
N.
Josseaume
, et al
2020
.
Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions.
J. Immunother. Cancer
8
:
e001054
.
92.
Lang
P. A.
,
S. Q.
Crome
,
H. C.
Xu
,
K. S.
Lang
,
L.
Chapatte
,
E. K.
Deenick
,
M.
Grusdat
,
A. A.
Pandyra
,
V. I.
Pozdeev
,
R.
Wang
, et al
2020
.
NK cells regulate CD8+ T cell mediated autoimmunity.
Front. Cell. Infect. Microbiol.
10
:
36
.
93.
Kim
H. S.
,
J.-H.
Jang
,
M. B.
Lee
,
I. D.
Jung
,
Y. M.
Kim
,
Y. M.
Park
,
W. S.
Choi
.
2016
.
A novel IL-10-producing innate lymphoid cells (ILC10) in a contact hypersensitivity mouse model.
BMB Rep.
49
:
293
296
.
94.
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
.
95.
Ghaedi
M.
,
F.
Takei
.
2021
.
Innate lymphoid cell development.
J. Allergy Clin. Immunol.
147
:
1549
1560
.
96.
Wang
S.
,
Y.
Qu
,
P.
Xia
,
Y.
Chen
,
X.
Zhu
,
J.
Zhang
,
G.
Wang
,
Y.
Tian
,
J.
Ying
,
Z.
Fan
.
2020
.
Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer. [Published erratum appears in 2021 Cell Res. 31: 241]. [Published erratum appears in 2020 Cell Res.30: 630].
Cell Res.
30
:
610
622
.
97.
Cao
Q.
,
R.
Wang
,
Y.
Wang
,
Z.
Niu
,
T.
Chen
,
C.
Wang
,
L.
Jin
,
Q.
Huang
,
Q.
Li
,
X. M.
Wang
, et al
2020
.
Regulatory innate lymphoid cells suppress innate immunity and reduce renal ischemia/reperfusion injury.
Kidney Int.
97
:
130
142
.
98.
O’Connor
M. H.
,
R.
Muir
,
M.
Chakhtoura
,
M.
Fang
,
E.
Moysi
,
S.
Moir
,
A. J.
Carey
,
A.
Terk
,
C. N.
Nichols
,
T.
Metcalf
, et al
2021
.
A follicular regulatory innate lymphoid cell population impairs interactions between germinal center Tfh and B cells.
Commun. Biol.
4
:
563
.
99.
Melo-Gonzalez
F.
,
H.
Kammoun
,
E.
Evren
,
E. E.
Dutton
,
M.
Papadopoulou
,
B. M.
Bradford
,
C.
Tanes
,
F.
Fardus-Reid
,
J. R.
Swann
,
K.
Bittinger
, et al
2019
.
Antigen-presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal bacteria.
J. Exp. Med.
216
:
728
742
.
100.
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
.
101.
Doherty
T. A
.
2014
.
At the bench: understanding group 2 innate lymphoid cells in disease.
J. Leukoc. Biol.
97
:
455
467
.
102.
Neill
D. R.
,
S. H.
Wong
,
A.
Bellosi
,
R. J.
Flynn
,
M.
Daly
,
T. K. A.
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
.
103.
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
.
104.
Morita
H.
,
T.
Kubo
,
B.
Rückert
,
A.
Ravindran
,
M. B.
Soyka
,
A. O.
Rinaldi
,
K.
Sugita
,
M.
Wawrzyniak
,
P.
Wawrzyniak
,
K.
Motomura
, et al
2019
.
Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid.
J. Allergy Clin. Immunol.
143
:
2190
2201.e9
.
105.
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
.
106.
Björklund
Å. K.
,
M.
Forkel
,
S.
Picelli
,
V.
Konya
,
J.
Theorell
,
D.
Friberg
,
R.
Sandberg
,
J.
Mjösberg
.
2016
.
The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing.
Nat. Immunol.
17
:
451
460
.
107.
Howard
E.
,
G.
Lewis
,
L.
Galle-Treger
,
B. P.
Hurrell
,
D. G.
Helou
,
P.
Shafiei-Jahani
,
J. D.
Painter
,
G. A.
Muench
,
P.
Soroosh
,
O.
Akbari
.
2021
.
IL-10 production by ILC2s requires Blimp-1 and cMaf, modulates cellular metabolism, and ameliorates airway hyperreactivity.
J. Allergy Clin. Immunol.
147
:
1281
1295.e5
.
108.
Boonpiyathad
T.
,
P.
Tantilipikorn
,
K.
Ruxrungtham
,
P.
Pradubpongsa
,
W.
Mitthamsiri
,
A.
Piedvache
,
P.
Thantiworasit
,
S.
Sirivichayakul
,
A.
Jacquet
,
N.
Suratannon
, et al
2021
.
IL-10-producing innate lymphoid cells increased in patients with house dust mite allergic rhinitis following immunotherapy.
J. Allergy Clin. Immunol.
147
:
1507
1510.e8
.
109.
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
.
110.
Baban
B.
,
M.
Braun
,
H.
Khodadadi
,
A.
Ward
,
K.
Alverson
,
A.
Malik
,
K.
Nguyen
,
S.
Nazarian
,
D. C.
Hess
,
S.
Forseen
, et al
2021
.
AMPK induces regulatory innate lymphoid cells after traumatic brain injury.
JCI Insight
6
:
e126766
.
111.
Xu
M.
,
M.
Pokrovskii
,
Y.
Ding
,
R.
Yi
,
C.
Au
,
O. J.
Harrison
,
C.
Galan
,
Y.
Belkaid
,
R.
Bonneau
,
D. R.
Littman
.
2018
.
c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. [Published erratum appears in 2019 Nature 566: E7].
Nature
554
:
373
377
.
112.
Gabryšová
L.
,
M.
Alvarez-Martinez
,
R.
Luisier
,
L. S.
Cox
,
J.
Sodenkamp
,
C.
Hosking
,
D.
Pérez-Mazliah
,
C.
Whicher
,
Y.
Kannan
,
K.
Potempa
, et al
2018
.
c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. [Published erratum appears in 2019 Nature 20: 374].
Nat. Immunol.
19
:
497
507
.
113.
Neumann
C.
,
F.
Heinrich
,
K.
Neumann
,
V.
Junghans
,
M. F.
Mashreghi
,
J.
Ahlers
,
M.
Janke
,
C.
Rudolph
,
N.
Mockel-Tenbrinck
,
A. A.
Kühl
, et al
2014
.
Role of Blimp-1 in programing Th effector cells into IL-10 producers.
J. Exp. Med.
211
:
1807
1819
.
114.
Martins
G. A.
,
L.
Cimmino
,
M.
Shapiro-Shelef
,
M.
Szabolcs
,
A.
Herron
,
E.
Magnusdottir
,
K.
Calame
.
2006
.
Transcriptional repressor Blimp-1 regulates T cell homeostasis and function.
Nat. Immunol.
7
:
457
465
.
115.
Montes de Oca
M.
,
R.
Kumar
,
F.
de Labastida Rivera
,
F. H.
Amante
,
M.
Sheel
,
R. J.
Faleiro
,
P. T.
Bunn
,
S. E.
Best
,
L.
Beattie
,
S. S.
Ng
, et al
2016
.
Blimp-1-dependent IL-10 production by Tr1 cells regulates TNF-mediated tissue pathology. [Published erratum appears in 2016 PLoS Pathog. 12: e1005460].
PLoS Pathog.
12
:
e1005398
.
116.
Ishiguro
A.
,
K. S.
Spirin
,
M.
Shiohara
,
A.
Tobler
,
A. F.
Gombart
,
M. A.
Israel
,
J. D.
Norton
,
H. P.
Koeffler
.
1996
.
Id2 expression increases with differentiation of human myeloid cells.
Blood
87
:
5225
5231
.
117.
Hacker
C.
,
R. D.
Kirsch
,
X.-S.
Ju
,
T.
Hieronymus
,
T. C.
Gust
,
C.
Kuhl
,
T.
Jorgas
,
S. M.
Kurz
,
S.
Rose-John
,
Y.
Yokota
,
M.
Zenke
.
2003
.
Transcriptional profiling identifies Id2 function in dendritic cell development.
Nat. Immunol.
4
:
380
386
.
118.
Morrow
M. A.
,
E. W.
Mayer
,
C. A.
Perez
,
M.
Adlam
,
G.
Siu
.
1999
.
Overexpression of the Helix-Loop-Helix protein Id2 blocks T cell development at multiple stages.
Mol. Immunol.
36
:
491
503
.
119.
Fujimoto
S.
,
T.
Ikawa
,
T.
Kina
,
Y.
Yokota
.
2007
.
Forced expression of Id2 in fetal thymic T cell progenitors allows some of their progeny to adopt NK cell fate.
Int. Immunol.
19
:
1175
1182
.
120.
Orecchioni
M.
,
Y.
Ghosheh
,
A. B.
Pramod
,
K.
Ley
.
2019
.
Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS–) vs. alternatively activated macrophages. [Published erratum appears in 2020 Front Immunol. 11: 234].
Front. Immunol.
10
:
1084
.
121.
Jablonski
K. A.
,
S. A.
Amici
,
L. M.
Webb
,
J. D.
Ruiz-Rosado
,
P. G.
Popovich
,
S.
Partida-Sanchez
,
M.
Guerau-de-Arellano
.
2015
.
Novel markers to delineate murine M1 and M2 macrophages.
PLoS One
10
:
e0145342
.

The authors have no financial conflicts of interest.