Th17 cells are an effector lineage of CD4 T cells that can contribute to protection against microbial pathogens and to the development of harmful autoimmune and inflammatory conditions. An increasing number of studies suggests that Th17 cells play an important protective role in mobilizing host immunity to extracellular and intracellular microbial pathogens, such as Candida and Salmonella. Furthermore, the generation of Th17 cells is heavily influenced by the normal microbial flora, highlighting the complex interplay among harmless microbes, pathogens, and host immunity in the regulation of pathogen-specific Th17 responses. In this article, we review the current understanding of microbe-induced Th17 cells in the context of infectious and inflammatory disease.

Naive CD4 T cells exit the thymus and, in the absence of cognate Ag, repeatedly travel through peripheral blood and lymphatic vessels (1). Initial activation of CD4 T cells occurs within secondary lymphoid organs and requires recognition of antigenic peptides presented by MHC class II molecules on the surface of migrating or resident dendritic cells (2). Throughout the period of activation, CD4 T cells integrate signals from the TCR, costimulatory molecules, and cytokine receptors to ultimately determine which effector capabilities will be acquired (3). Thus, APCs and the local stimulating environment can shape the development of the effector T cell pool in an appropriate manner. In infectious disease models, this plasticity allows the development of pathogen-specific effector T cells that are tailored to combat different types of microbial pathogens.

Heterogeneity within the CD4 T cell compartment was initially reported by investigators studying Ab or delayed-type hypersensitivity responses after immunization with protein or bacterial products (46). This led to the discovery of CD4 Th1 and Th2 populations, which represent distinct T effector lineages with differential ability to produce antimicrobial cytokines (7, 8). Th1 cells are defined by ex/Centerpression of the transcription factor T-bet and secretion of IFN-γ, a cytokine that can activate macrophages to kill intracellular pathogens (9). Th2 cells are characterized by the expression of GATA-3 and the production of IL-4, IL-5, and IL-13, cytokines that are critical for eradication of many extracellular parasites (10, 11). Although the definition of Th1 and Th2 provided an important conceptual framework for understanding effector CD4 T cell development, a much wider range of effector lineages is now appreciated (12). In this review, we focus on the development of Th17 cells and how they interact with the microbes that colonize or infect the mammalian host.

Th1 and Th2 differentiation can be examined by in vitro stimulation of naive Ag-specific CD4 T cells in the presence of IL-12 and IL-4, cytokines that are normally induced by the innate immune response to microbial ligands (13). In one particular study, it was observed that the replacement of IL-12 with Borrelia burgdorferi lysate, mycobacterial lysate, or IL-6 caused the development of effector CD4 T cells that produced IL-17 (14). Furthermore, these IL-17–producing CD4 T cells coexpressed TNF-α and GM-CSF, but they did not express IFN-γ or IL-4, suggesting the development of an effector subset distinct from Th1 or Th2. Further evidence that IL-17–producing cells represented a novel subset came from the observation that IL-23 could promote the development of these cells (15). IL-23 is a member of the four-chain-long helix bundle family of cytokines, which includes IL-6 and IL-12. IL-23 shares the p40 subunit with IL-12 but has a unique p19 subunit (16), and the discovery that models of autoimmunity were dependent on IL-23p19 rather than IL-12p35 initiated a re-evaluation of prior studies using p40-deficient animals (17, 18). The real notoriety of Th17 cells came with the discovery that IL-17–producing T cells, driven by IL-23, are the major contributors to pathogenesis of autoimmune inflammatory diseases (19). Previously, Th1 cells were thought to drive autoimmunity, but many subsequent studies in mouse models and human disease brought the realization that Th17 cells represent a new and important target for therapy of psoriasis, inflammatory bowel disease, uveitis, multiple sclerosis, and arthritis (20, 21). Genetic polymorphisms or deficiencies that modulate the IL-23/Th17 axis, including IL-23R, CARD9, STAT3, and AIRE, result in enhanced susceptibility to inflammatory disease, and the importance of Th17-related targets in human autoimmunity is now being validated in clinical trials targeting p40, IL-17, IL-17RA, and IL-23(p19).

Initiating autoimmune disease is clearly not the raison d’être of IL-17–producing CD4 T cells, and a more complete picture is now emerging of how Th17 cells contribute to host defense against microbial pathogens (22, 23). Several studies detected IL-17–producing CD4 T cells in diverse infectious disease models, and a theme that has emerged is that this lineage contributes to host defense against extracellular microbes (24, 25). The cytokines produced by Th17 cells are well suited to this role: IL-17 and TNF-α can synergize to activate epithelial cell production of antimicrobial peptides, monocyte-recruiting chemokines, whereas G-CSF additionally drives granulopoiesis (26). IL-22 produced by Th17 cells promotes the production of antimicrobial peptides and the proliferation of epithelial cells, which can be important for repairing damage inflicted by microbial invasion (27). GM-CSF and IL-17 also activate monocytes and neutrophils to promote phagocytosis of microbes and clearance of the infection. However, it should be emphasized that Th17 cell development is not limited to extracellular bacterial infections, and these cells have been observed in numerous intracellular bacterial, viral, and extracellular parasite infection models (2830). The potent ability of Th17 cells to elicit chemokine production in tissue sites, including Th1-recruiting chemokines, such as CXCL13, makes them ideally suited as first responders during reinfection (31). In addition, IL-17 can promote IL-12 production through regulation of IL-10 in dendritic cells during infection with Mycobacterium tuberculosis (32) and Francisella tularensis (33), two intracellular infections that require both IL-17A and Th1 responses for optimal pathogen control. Thus, although Th17 cells are often associated with extracellular infection, they are a CD4 lineage that is commonly elicited in response to a wide variety of pathogens. In the latter half of this review, we focus on Th17 immunity to examples of extracellular and intracellular pathogens: Candida and Salmonella.

Th17 cells were officially recognized as a distinct subset of Th cells following seminal studies demonstrating that differentiation of IL-17–producing CD4+ T cells is dependent on STAT3 and RORγt expression but independent of putative Th1 or Th2 transcription factors (3436). TGF-β, IL-6, and IL-21 drive the activation of STAT3, which can subsequently activate RORγt (37, 38) and drives the expression of IL-23R (39). IL-23 subsequently acts on these early developing Th17 cells to drive effector cell differentiation and expansion (40). Some controversy persists over the precise role of TGF-β in Th17 cell differentiation in mice and humans. TGF-β and its receptor are both required for T cell-intrinsic Th17 development in mouse models of colitis and encephalomyelitis (4143). However, high concentrations of TGF-β and IL-6 stimulate production of IL-10 and inhibit the pathogenic functions of murine Th17 cells activated in vitro (44, 45). In addition, human Th17 cell differentiation does not seem to require the addition of TGF-β, which may even suppress their development (46, 47).

Classical TLR activation drives the production of a variety of inflammatory cytokines, but the triggering of receptors of the C-type lectin family (CLRs) seems to provide a more specific Th17-inducing signal (Fig. 1). Fungal components bind to Dectin1, Dectin2, and Mincle, leading to recruitment of the tyrosine kinase Syk, activation of the adaptor CARD9, and downstream signaling via NF-κB, resulting in upregulation of IL-23, IL-1, IL-6, and TNF (4851). Humans with loss-of-function mutations in CARD9 develop chronic mucocutaneous candidiasis and have reduced Th17 cells (52). Microbial ligands that induce Th17 responses via TLRs and CLRs have primarily been defined for Candida, but similar ligands likely exist for bacteria and viral pathogens. Mycobacterial cord factor was recently shown to bind to Mincle and activate Syk/CARD9 signaling to promote Th17 responses in a bacillus Calmette-Guérin vaccine model (53), and this may explain the efficacy of heat-killed Mycobacterium bovis as a Th17-inducing adjuvant. Furthermore, yeast, Mycobacterium, and heat-killed Streptococcus pneumoniae activate TLR2 to promote Th17 development (54, 55), and flagellin expression by segmented filamentous bacteria also induces intestinal Th17 responses (56). Although CLR signaling can occur independently of TLRs, collaboration between TLRs and Dectin1 signaling enhances the production of IL-6 and IL-23 (51, 57); conversely, it was proposed that CLR signaling modulates TLR signaling to downregulate the production of IL-12 and favor Th17-inducing cytokines, such as IL-23 (Fig. 1 and Refs. 49, 57, 58).

FIGURE 1.

Induction of Th17-promoting cytokines by microbial products. C-type lectins Mincle, Dectin1, and Dectin2, as well as mannose receptor, are expressed on dendritic cells and macrophages and recognize fungal and mycobacterial components to activate Syk kinase and the CARD9 adaptor, leading to production of inflammatory cytokines that promote Th17 development in naive T cells. TLRs also recognize microbial products and induce production of both Th17- and Th1-promoting cytokines, including IL-23 and IL-12. CLR signaling modulates TLR signaling to downregulate Th1-promoting conditions and favor Th17-promoting conditions; thus, CLRs and TLRs cooperate to fine-tune the type of Th response elicited.

FIGURE 1.

Induction of Th17-promoting cytokines by microbial products. C-type lectins Mincle, Dectin1, and Dectin2, as well as mannose receptor, are expressed on dendritic cells and macrophages and recognize fungal and mycobacterial components to activate Syk kinase and the CARD9 adaptor, leading to production of inflammatory cytokines that promote Th17 development in naive T cells. TLRs also recognize microbial products and induce production of both Th17- and Th1-promoting cytokines, including IL-23 and IL-12. CLR signaling modulates TLR signaling to downregulate Th1-promoting conditions and favor Th17-promoting conditions; thus, CLRs and TLRs cooperate to fine-tune the type of Th response elicited.

Close modal

It has become increasingly clear that the resident bacterial population (the “microbiome”) in any given individual can profoundly impact one’s overall health and susceptibility to inflammatory and infectious disease (59). The microbiome comprises bacterial, viral, and eukaryote species that continuously colonize host mucosal and epithelial surfaces. Although these microbes can be found associated with the skin, lung, genital, and oral cavity, we focus our discussion on the intestinal tract (60). It has long been considered that tolerance is induced to these constituent microbes, allowing them to reside in these various tissue sites without inducing inflammation (61). In fact, inflammatory bowel disease most likely arises as a consequence of developing an inappropriate immune response against host commensal flora (62). However, it is becoming increasingly clear that subclinical responses induced against microbes residing in the gut may also have far-reaching consequences throughout the body.

Endogenous microbial flora play a major role in the differentiation of Th17 cells and regulatory T cells in the small intestine under steady-state conditions, and antibiotic treatment or the complete absence of bacterial flora reduces the number of Th17 cells in the gut (63). Indeed, recolonization of the intestine with Clostridia-related commensal species, and segmented filamentous bacteria (SFB) in particular, is sufficient to induce CD4 T cells that produce IL-17 and IL-22, as well as other CD4 Th lineages (64, 65). SFB are Gram-positive anaerobes that are normally tightly attached to epithelial cells and are highly dependent on the host for many essential nutrients (66, 67). It is now apparent that intestinal flora, and especially SFB, can strongly modulate the induction of Th17 responses throughout the body and, thereby, regulate the susceptibility of mice to arthritis (68), colitis (69, 70), diabetes (71), and experimental autoimmune encephalomyelitis (72).

The specific bacterial products that drive homeostatic intestinal Th17 differentiation have not been well defined; however, flagellins are attractive candidates because they are expressed by SFB, recognized by TLR5-expressing intestinal phagocytes, induce IL-23 from CD103+ dendritic cells, and drive Th17 responses to enteric pathogens (56, 66, 67, 73, 74). Recent data suggest that IL-1β production by intestinal macrophages is induced by TLR recognition of microbial flora and that IL-1R signaling on intestinal T cells is required for homeostatic differentiation of intestinal Th17 cells (75). It remains to be determined how local production of IL-1β in the lamina propria directly affects naive T cell differentiation within secondary lymphoid tissues, but it seems possible that Peyer’s patches could play a major role because naive CD4 T cells in this location are closely associated with SFB and lamina propria macrophages (64).

It is possible that the development of inflammatory Th17 responses to enteric pathogens differs substantially from the homeostatic development of Th17 cells in response to microbial flora. Although IL-6 is reported to play a key role in Th17 development, this cytokine does not seem to be required for intestinal Th17 development under steady-state conditions (7577). Th17 cells generated in the presence of IL-23 or IL-6/TGF-β develop different functional and pathogenic potential in autoimmune models (40, 45). Furthermore, recent data show that human Th17 cells induced by Candida albicans or Staphylococcus aureus have differential capacity to produce IFN-γ or IL-10 (78). Therefore, a degree of functional heterogeneity may exist between steady-state Th17 and pathogen-specific Th17 cells, between Th17 cells induced by different classes of microbial pathogens, or between Th17 cells that are elicited at different anatomical sites. To complicate matters further, enteric pathogens, such as Salmonella and Citrobacter, can also modify the composition of the microbial flora (79, 80) and, as a result, may indirectly modulate steady-state development of Th17 cells.

A requirement for IL-17 was demonstrated in host resistance to extracellular pathogens, such as C. albicans (81). Mice with a deficiency in IL-17A or IL-17RA are more susceptible to i.v. Candida infection (82, 83), and IL-17RA– and IL-17RC–deficient mice are unable to clear oral infection with C. albicans (84, 85). In contrast, neither IL-17F nor IL-22 is essential for host resistance to Candida infection (83, 84, 86). In the oral infection model, mice lacking IL-17RA signaling have decreased neutrophil infiltration (84), confirming a key role for IL-17A in recruiting phagocytes to the local site of infection. Candida-infected IL-23–deficient mice or IL-17RA–deficient mice also have reduced production of antimicrobial proteins, and saliva from these mice show reduced bactericidal activity (84). Thus, IL-17 plays an indirect role in the defense against extracellular pathogens by recruiting phagocytes and inducing antimicrobial peptides at the site of infection. A key role for IL-17 in fungal defense was also documented by genetic analysis of patients with increased susceptibility to chronic mucocutaneous candidiasis (87). Patients with autosomal-recessive IL-17RA or autosomal-dominant IL-17F deficiency experience recurrent Candida infections of the oral and genital mucosa (88). Similarly, patients with a gain-of-function mutation in STAT1 have increased responses to cytokines that impair the development of Th17 cells and, as a result, are highly susceptible to chronic mucocutaneous candidiasis (89). Interestingly, patients with IL-17F deficiency produce a mutant IL-17F that can still form a heterodimer with IL-17A or wild-type IL-17F but with reduced functional activity (88); thus, IL-17A, rather than IL-17F, may be critical for defense against Candida in humans. Together, these murine and human studies demonstrate that production of IL-17 at the site of fungal infection plays a key role in the resolution or susceptibility to disease. Studies with many other microbes have established the paradigm that Th17 cytokines play a major role in mobilizing local host defense against infection with extracellular pathogens (23, 90).

Salmonella is a facultative intracellular pathogen that causes serious gastrointestinal and systemic infections (91). Like other intramacrophage pathogens, Th1 cells are essential for protective immunity, and mice with a genetic deficiency in T-bet or IFN-γ are unable to resolve Salmonella infection (92, 93). However, recent data demonstrate that Th17 cells develop during Salmonella infection and play an important role in host defense in the intestine.

Th17 cells can be induced when mice are infected with Salmonella via nonphysiological routes; however, the population is typically small, and mice lacking IL-23R p19 or IL-17A experience only a minor delay in resolving primary infection (94, 95). In contrast, there is accumulating evidence that Th17 cells and associated cytokines play an important role in resistance to mucosal Salmonella infections (91, 96). Using a ligated loop model in rhesus macaques, it was noted that IL-22, IL-17, and IL-17–responsive genes were rapidly transcribed after Salmonella infection, and prior depletion of CD4 T cells by SIV infection reduced this response considerably (97). SIV infection also reduced IL-17–producing CD4 T cells in the lamina propria and correlated with enhanced dissemination of Salmonella to mesenteric lymph nodes (97). This is an important finding because patients with HIV are highly susceptible to disseminated Salmonella infections, and the loss of protective Th17 cells in the intestine may explain this susceptibility (96, 98). Consistent with this idea, patients with a primary genetic deficiency in Th17 development are also highly susceptible to disseminated Salmonella infections (96).

Given the rapid induction of Th17 cytokines in the ligated loop model, it is unlikely that this is due to Salmonella-specific Th17 cells. It is more likely that intestinal Th17 cells are activated in a nonspecific fashion in response to IL-1 or other inflammatory cytokines. Indeed, the early Th17 response to intestinal Salmonella infection requires expression of Myd88 and IL-1R (99). However, Nod1, Nod2, and the production of IL-6 can also cause rapid innate activation of Th17 cells (100), although IL-6 was dispensable in a different infection model (101). Noncognate induction of effector T cells blurs the lines between innate and adaptive immunity to infection but is a common feature of immunity to Salmonella. Indeed, effector Th1 CD4 and CD8 T cells in Salmonella-infected mice rapidly secrete IFN-γ in response to innate stimuli (102, 103).

This rapid innate response does not mean that Salmonella-specific Th17 cells cannot also contribute to immunity at mucosal surfaces. A recent report documented simultaneous development of Salmonella-specific Th17 and Th1 cells in the intestine and spleen, respectively, after oral infection (74). These anatomically segregated Th17 and Th1 responses targeted different Salmonella Ags that were highly expressed in each tissue. The factors responsible for driving Salmonella-specific Th17 cell development in the intestine have not been clearly defined, but previous reports showed that dendritic cells conditioned with Salmonella direct Th17 and Th1 development in vitro (104, 105), and recent data show an intriguing role for B cell-derived IL-6 in the generation of Th17 cells (106). Interestingly, Salmonella-specific Th17 cells recognize Salmonella flagellin (74), an Ag that has intrinsic stimulatory capabilities and induces IL-1 and IL-6 production (107, 108). Therefore, it is possible that innate recognition of flagellin via TLR5 and/or NLRC4 is responsible for driving Salmonella-specific Th17 development in the intestine during infection.

As noted above, intestinal Th17 cells play a key role in early protective immunity by limiting dissemination of Salmonella to the mesenteric lymph nodes (97). However, it should be emphasized that there is no evidence for Th17 cells playing a protective role after Salmonella have spread to systemic tissues. Instead, intestinal Th17 cells prevent Salmonella dissemination using similar mechanisms implicated in immunity to extracellular bacteria. Intestinal epithelial cells can respond to local IL-17 and IL-22 in vitro by increasing production of antimicrobial proteins and chemokines during Salmonella infection (97, 109). These include antibacterial proteins, such as inducible NO synthase, mucin, calprotectin, RegIIIγ, and lipocalin-2, which can directly or indirectly limit bacterial growth (110). The chemokine CCL20 is also prominently produced in response to IL-17 and IL-22 and can recruit immature CCR6+ dendritic cells and presumably initiate adaptive responses (109, 111). The production of G-CSF and CXC chemokines also recruits neutrophils to the intestine, and these engulf bacteria that have crossed the epithelial barrier (112).

Thus, the mechanism of Th17 defense against Salmonella penetration is similar to defense against extracellular bacteria. Indeed, although it is conceptually appealing to think of Th17 cells protecting against extracellular organisms and Th1 cells combating intracellular organisms, data from the Salmonella model suggest that Th17 cells can be highly active against intracellular organisms during the initial phase of trans-epithelial entry. Because most other microbial pathogens also have some degree of variation in life cycle stage or tissue tropism, a heterogenous T effector response is probably the norm rather than the exception.

We have discussed the role of microbes in the differentiation of Th17 cells in both autoimmune and infectious disease models and focused on Candida and Salmonella as two examples of pathogens that induce Th17 responses. It is apparent that the differentiation of Th17 cells is surprisingly complex, involving the elicitation of multiple cytokines, most likely as a result of several microbial ligands activating receptors on dendritic cells or other innate cells. There is also a degree of functional heterogeneity within the Th17 lineage that may mean that this lineage is adapted to fit the immune response to different pathogens or immunity at different anatomical sites. Greater understanding of how this complexity and functional heterogeneity can impact the specific effector response against different classes of pathogens is now required. Furthermore, the tripartite interactions that occur among host, microbiome, and microbial pathogen have not been examined in any depth, and much greater understanding of how communication flows between each of these players in the regulation of Th17 cell development should be forthcoming. However, this may be challenging technically because it likely will require the definition of endogenous flora as a variable within many current experimental systems. Furthermore, the specific cross-talk that has evolved between pathogenic and nonpathogenic organisms in the induction of human Th17 cells may be difficult to replicate in animal models unless greater attention is paid to the use of natural animal pathogens and routes of infection. However, greater understanding of these issues may lead to the development of vaccines and therapeutics for important infectious and inflammatory diseases.

This work was supported by Grants AI073672, AI055743, and HL112685 from the National Institutes of Health (to S.J.M.).

Abbreviations used in this article:

CLR

receptor of the C-type lectin family

SFB

segmented filamentous bacteria.

1
Gowans
J. L.
,
Knight
E. J.
.
1964
.
The route of re-circulation of lymphocytes in the rat.
Proc. R. Soc. Lond. B Biol. Sci.
159
:
257
282
.
2
Jenkins
M. K.
,
Khoruts
A.
,
Ingulli
E.
,
Mueller
D. L.
,
McSorley
S. J.
,
Reinhardt
R. L.
,
Itano
A.
,
Pape
K. A.
.
2001
.
In vivo activation of antigen-specific CD4 T cells.
Annu. Rev. Immunol.
19
:
23
45
.
3
Zhu
J.
,
Yamane
H.
,
Paul
W. E.
.
2010
.
Differentiation of effector CD4 T cell populations (*).
Annu. Rev. Immunol.
28
:
445
489
.
4
Parish
C. R.
,
Liew
F. Y.
.
1972
.
Immune response to chemically modified flagellin. 3. Enhanced cell-mediated immunity during high and low zone antibody tolerance to flagellin.
J. Exp. Med.
135
:
298
311
.
5
Liew
F. Y.
,
Parish
C. R.
.
1974
.
Lack of a correlation between cell-mediated immunity to the carrier and the carrier-hapten helper effect.
J. Exp. Med.
139
:
779
784
.
6
Marrack
P. C.
,
Kappler
J. W.
.
1975
.
Antigen-specific and nonspecific mediators of T cell/B cell cooperation. I. Evidence for their production by different T cells.
J. Immunol.
114
:
1116
1125
.
7
Mosmann
T. R.
,
Cherwinski
H.
,
Bond
M. W.
,
Giedlin
M. A.
,
Coffman
R. L.
.
1986
.
Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.
J. Immunol.
136
:
2348
2357
.
8
Scott
P.
,
Pearce
E.
,
Cheever
A. W.
,
Coffman
R. L.
,
Sher
A.
.
1989
.
Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease.
Immunol. Rev.
112
:
161
182
.
9
Szabo
S. J.
,
Sullivan
B. M.
,
Stemmann
C.
,
Satoskar
A. R.
,
Sleckman
B. P.
,
Glimcher
L. H.
.
2002
.
Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells.
Science
295
:
338
342
.
10
Zhang
D. H.
,
Cohn
L.
,
Ray
P.
,
Bottomly
K.
,
Ray
A.
.
1997
.
Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene.
J. Biol. Chem.
272
:
21597
21603
.
11
Zheng
W.
,
Flavell
R. A.
.
1997
.
The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.
Cell
89
:
587
596
.
12
Zhu
J.
,
Paul
W. E.
.
2010
.
Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors.
Immunol. Rev.
238
:
247
262
.
13
Hsieh
C. S.
,
Heimberger
A. B.
,
Gold
J. S.
,
O’Garra
A.
,
Murphy
K. M.
.
1992
.
Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system.
Proc. Natl. Acad. Sci. USA
89
:
6065
6069
.
14
Infante-Duarte
C.
,
Horton
H. F.
,
Byrne
M. C.
,
Kamradt
T.
.
2000
.
Microbial lipopeptides induce the production of IL-17 in Th cells.
J. Immunol.
165
:
6107
6115
.
15
Aggarwal
S.
,
Ghilardi
N.
,
Xie
M. H.
,
de Sauvage
F. J.
,
Gurney
A. L.
.
2003
.
Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.
J. Biol. Chem.
278
:
1910
1914
.
16
Oppmann
B.
,
Lesley
R.
,
Blom
B.
,
Timans
J. C.
,
Xu
Y.
,
Hunte
B.
,
Vega
F.
,
Yu
N.
,
Wang
J.
,
Singh
K.
, et al
.
2000
.
Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.
Immunity
13
:
715
725
.
17
Cua
D. J.
,
Sherlock
J.
,
Chen
Y.
,
Murphy
C. A.
,
Joyce
B.
,
Seymour
B.
,
Lucian
L.
,
To
W.
,
Kwan
S.
,
Churakova
T.
, et al
.
2003
.
Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
Nature
421
:
744
748
.
18
Murphy
C. A.
,
Langrish
C. L.
,
Chen
Y.
,
Blumenschein
W.
,
McClanahan
T.
,
Kastelein
R. A.
,
Sedgwick
J. D.
,
Cua
D. J.
.
2003
.
Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
J. Exp. Med.
198
:
1951
1957
.
19
Langrish
C. L.
,
Chen
Y.
,
Blumenschein
W. M.
,
Mattson
J.
,
Basham
B.
,
Sedgwick
J. D.
,
McClanahan
T.
,
Kastelein
R. A.
,
Cua
D. J.
.
2005
.
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
J. Exp. Med.
201
:
233
240
.
20
Bowman
E. P.
,
Chackerian
A. A.
,
Cua
D. J.
.
2006
.
Rationale and safety of anti-interleukin-23 and anti-interleukin-17A therapy.
Curr. Opin. Infect. Dis.
19
:
245
252
.
21
Strober
W.
,
Fuss
I. J.
.
2011
.
Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases.
Gastroenterology
140
:
1756
1767
.
22
Khader
S. A.
,
Gaffen
S. L.
,
Kolls
J. K.
.
2009
.
Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa.
Mucosal Immunol.
2
:
403
411
.
23
Curtis
M. M.
,
Way
S. S.
.
2009
.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
126
:
177
185
.
24
Aujla
S. J.
,
Dubin
P. J.
,
Kolls
J. K.
.
2007
.
Th17 cells and mucosal host defense.
Semin. Immunol.
19
:
377
382
.
25
Gaffen
S. L.
,
Hernández-Santos
N.
,
Peterson
A. C.
.
2011
.
IL-17 signaling in host defense against Candida albicans.
Immunol. Res.
50
:
181
187
.
26
Iwakura
Y.
,
Ishigame
H.
,
Saijo
S.
,
Nakae
S.
.
2011
.
Functional specialization of interleukin-17 family members.
Immunity
34
:
149
162
.
27
Zelante
T.
,
Iannitti
R.
,
De Luca
A.
,
Romani
L.
.
2011
.
IL-22 in antifungal immunity.
Eur. J. Immunol.
41
:
270
275
.
28
Torrado
E.
,
Cooper
A. M.
.
2010
.
IL-17 and Th17 cells in tuberculosis.
Cytokine Growth Factor Rev.
21
:
455
462
.
29
Hartigan-O’Connor
D. J.
,
Hirao
L. A.
,
McCune
J. M.
,
Dandekar
S.
.
2011
.
Th17 cells and regulatory T cells in elite control over HIV and SIV.
Curr Opin HIV AIDS
6
:
221
227
.
30
Maizels
R. M.
,
Pearce
E. J.
,
Artis
D.
,
Yazdanbakhsh
M.
,
Wynn
T. A.
.
2009
.
Regulation of pathogenesis and immunity in helminth infections.
J. Exp. Med.
206
:
2059
2066
.
31
Khader
S. A.
,
Bell
G. K.
,
Pearl
J. E.
,
Fountain
J. J.
,
Rangel-Moreno
J.
,
Cilley
G. E.
,
Shen
F.
,
Eaton
S. M.
,
Gaffen
S. L.
,
Swain
S. L.
, et al
.
2007
.
IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.
Nat. Immunol.
8
:
369
377
.
32
Gopal
R.
,
Lin
Y.
,
Obermajer
N.
,
Slight
S.
,
Nuthalapati
N.
,
Ahmed
M.
,
Kalinski
P.
,
Khader
S. A.
.
2012
.
IL-23-dependent IL-17 drives Th1-cell responses following Mycobacterium bovis BCG vaccination.
Eur. J. Immunol.
42
:
364
373
.
33
Lin
Y.
,
Ritchea
S.
,
Logar
A.
,
Slight
S.
,
Messmer
M.
,
Rangel-Moreno
J.
,
Guglani
L.
,
Alcorn
J. F.
,
Strawbridge
H.
,
Park
S. M.
, et al
.
2009
.
Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis.
Immunity
31
:
799
810
.
34
Harrington
L. E.
,
Hatton
R. D.
,
Mangan
P. R.
,
Turner
H.
,
Murphy
T. L.
,
Murphy
K. M.
,
Weaver
C. T.
.
2005
.
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
Nat. Immunol.
6
:
1123
1132
.
35
Park
H.
,
Li
Z.
,
Yang
X. O.
,
Chang
S. H.
,
Nurieva
R.
,
Wang
Y. H.
,
Wang
Y.
,
Hood
L.
,
Zhu
Z.
,
Tian
Q.
,
Dong
C.
.
2005
.
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
Nat. Immunol.
6
:
1133
1141
.
36
Ivanov
I. I.
,
McKenzie
B. S.
,
Zhou
L.
,
Tadokoro
C. E.
,
Lepelley
A.
,
Lafaille
J. J.
,
Cua
D. J.
,
Littman
D. R.
.
2006
.
The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
Cell
126
:
1121
1133
.
37
Yang
X. O.
,
Panopoulos
A. D.
,
Nurieva
R.
,
Chang
S. H.
,
Wang
D.
,
Watowich
S. S.
,
Dong
C.
.
2007
.
STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.
J. Biol. Chem.
282
:
9358
9363
.
38
Yang
X. O.
,
Pappu
B. P.
,
Nurieva
R.
,
Akimzhanov
A.
,
Kang
H. S.
,
Chung
Y.
,
Ma
L.
,
Shah
B.
,
Panopoulos
A. D.
,
Schluns
K. S.
, et al
.
2008
.
T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.
Immunity
28
:
29
39
.
39
Zhou
L.
,
Ivanov
I. I.
,
Spolski
R.
,
Min
R.
,
Shenderov
K.
,
Egawa
T.
,
Levy
D. E.
,
Leonard
W. J.
,
Littman
D. R.
.
2007
.
IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
Nat. Immunol.
8
:
967
974
.
40
McGeachy
M. J.
,
Chen
Y.
,
Tato
C. M.
,
Laurence
A.
,
Joyce-Shaikh
B.
,
Blumenschein
W. M.
,
McClanahan
T. K.
,
O’Shea
J. J.
,
Cua
D. J.
.
2009
.
The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.
Nat. Immunol.
10
:
314
324
.
41
Li
M. O.
,
Wan
Y. Y.
,
Flavell
R. A.
.
2007
.
T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation.
Immunity
26
:
579
591
.
42
Acharya
M.
,
Mukhopadhyay
S.
,
Païdassi
H.
,
Jamil
T.
,
Chow
C.
,
Kissler
S.
,
Stuart
L. M.
,
Hynes
R. O.
,
Lacy-Hulbert
A.
.
2010
.
αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice.
J. Clin. Invest.
120
:
4445
4452
.
43
Gutcher
I.
,
Donkor
M. K.
,
Ma
Q.
,
Rudensky
A. Y.
,
Flavell
R. A.
,
Li
M. O.
.
2011
.
Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation.
Immunity
34
:
396
408
.
44
McGeachy
M. J.
,
Bak-Jensen
K. S.
,
Chen
Y.
,
Tato
C. M.
,
Blumenschein
W.
,
McClanahan
T.
,
Cua
D. J.
.
2007
.
TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.
Nat. Immunol.
8
:
1390
1397
.
45
Ghoreschi
K.
,
Laurence
A.
,
Yang
X. P.
,
Tato
C. M.
,
McGeachy
M. J.
,
Konkel
J. E.
,
Ramos
H. L.
,
Wei
L.
,
Davidson
T. S.
,
Bouladoux
N.
, et al
.
2010
.
Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling.
Nature
467
:
967
971
.
46
Boniface
K.
,
Blom
B.
,
Liu
Y. J.
,
de Waal Malefyt
R.
.
2008
.
From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited.
Immunol. Rev.
226
:
132
146
.
47
Annunziato
F.
,
Romagnani
S.
.
2011
.
Mouse T helper 17 phenotype: not so different than in man after all.
Cytokine
56
:
112
115
.
48
Mills
K. H.
2011
.
TLR-dependent T cell activation in autoimmunity.
Nat. Rev. Immunol.
11
:
807
822
.
49
Lyakh
L.
,
Trinchieri
G.
,
Provezza
L.
,
Carra
G.
,
Gerosa
F.
.
2008
.
Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans.
Immunol. Rev.
226
:
112
131
.
50
Kerrigan
A. M.
,
Brown
G. D.
.
2011
.
Syk-coupled C-type lectins in immunity.
Trends Immunol.
32
:
151
156
.
51
LeibundGut-Landmann
S.
,
Gross
O.
,
Robinson
M. J.
,
Osorio
F.
,
Slack
E. C.
,
Tsoni
S. V.
,
Schweighoffer
E.
,
Tybulewicz
V.
,
Brown
G. D.
,
Ruland
J.
,
Reis e Sousa
C.
.
2007
.
Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.
Nat. Immunol.
8
:
630
638
.
52
Glocker
E. O.
,
Hennigs
A.
,
Nabavi
M.
,
Schäffer
A. A.
,
Woellner
C.
,
Salzer
U.
,
Pfeifer
D.
,
Veelken
H.
,
Warnatz
K.
,
Tahami
F.
, et al
.
2009
.
A homozygous CARD9 mutation in a family with susceptibility to fungal infections.
N. Engl. J. Med.
361
:
1727
1735
.
53
Schoenen
H.
,
Bodendorfer
B.
,
Hitchens
K.
,
Manzanero
S.
,
Werninghaus
K.
,
Nimmerjahn
F.
,
Agger
E. M.
,
Stenger
S.
,
Andersen
P.
,
Ruland
J.
, et al
.
2010
.
Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate.
J. Immunol.
184
:
2756
2760
.
54
Aliahmadi
E.
,
Gramlich
R.
,
Grützkau
A.
,
Hitzler
M.
,
Krüger
M.
,
Baumgrass
R.
,
Schreiner
M.
,
Wittig
B.
,
Wanner
R.
,
Peiser
M.
.
2009
.
TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23.
Eur. J. Immunol.
39
:
1221
1230
.
55
Olliver
M.
,
Hiew
J.
,
Mellroth
P.
,
Henriques-Normark
B.
,
Bergman
P.
.
2011
.
Human monocytes promote Th1 and Th17 responses to Streptococcus pneumoniae.
Infect. Immun.
79
:
4210
4217
.
56
Uematsu
S.
,
Jang
M. H.
,
Chevrier
N.
,
Guo
Z.
,
Kumagai
Y.
,
Yamamoto
M.
,
Kato
H.
,
Sougawa
N.
,
Matsui
H.
,
Kuwata
H.
, et al
.
2006
.
Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells.
Nat. Immunol.
7
:
868
874
.
57
Dennehy
K. M.
,
Willment
J. A.
,
Williams
D. L.
,
Brown
G. D.
.
2009
.
Reciprocal regulation of IL-23 and IL-12 following co-activation of Dectin-1 and TLR signaling pathways.
Eur. J. Immunol.
39
:
1379
1386
.
58
van Beelen
A. J.
,
Zelinkova
Z.
,
Taanman-Kueter
E. W.
,
Muller
F. J.
,
Hommes
D. W.
,
Zaat
S. A.
,
Kapsenberg
M. L.
,
de Jong
E. C.
.
2007
.
Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells.
Immunity
27
:
660
669
.
59
Clemente
J. C.
,
Ursell
L. K.
,
Parfrey
L. W.
,
Knight
R.
.
2012
.
The impact of the gut microbiota on human health: an integrative view.
Cell
148
:
1258
1270
.
60
Thiennimitr
P.
,
Winter
S. E.
,
Bäumler
A. J.
.
2012
.
Salmonella, the host and its microbiota.
Curr. Opin. Microbiol.
15
:
108
114
.
61
Mowat
A. M.
2003
.
Anatomical basis of tolerance and immunity to intestinal antigens.
Nat. Rev. Immunol.
3
:
331
341
.
62
Elson
C. O.
,
Cong
Y.
,
Sundberg
J.
.
2000
.
The C3H/HeJBir mouse model: a high susceptibility phenotype for colitis.
Int. Rev. Immunol.
19
:
63
75
.
63
Ivanov
I. I.
,
Frutos
Rde. L.
,
Manel
N.
,
Yoshinaga
K.
,
Rifkin
D. B.
,
Sartor
R. B.
,
Finlay
B. B.
,
Littman
D. R.
.
2008
.
Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine.
Cell Host Microbe
4
:
337
349
.
64
Gaboriau-Routhiau
V.
,
Rakotobe
S.
,
Lécuyer
E.
,
Mulder
I.
,
Lan
A.
,
Bridonneau
C.
,
Rochet
V.
,
Pisi
A.
,
De Paepe
M.
,
Brandi
G.
, et al
.
2009
.
The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses.
Immunity
31
:
677
689
.
65
Ivanov
I. I.
,
Atarashi
K.
,
Manel
N.
,
Brodie
E. L.
,
Shima
T.
,
Karaoz
U.
,
Wei
D.
,
Goldfarb
K. C.
,
Santee
C. A.
,
Lynch
S. V.
, et al
.
2009
.
Induction of intestinal Th17 cells by segmented filamentous bacteria.
Cell
139
:
485
498
.
66
Sczesnak
A.
,
Segata
N.
,
Qin
X.
,
Gevers
D.
,
Petrosino
J. F.
,
Huttenhower
C.
,
Littman
D. R.
,
Ivanov
I. I.
.
2011
.
The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment.
Cell Host Microbe
10
:
260
272
.
67
Prakash
T.
,
Oshima
K.
,
Morita
H.
,
Fukuda
S.
,
Imaoka
A.
,
Kumar
N.
,
Sharma
V. K.
,
Kim
S. W.
,
Takahashi
M.
,
Saitou
N.
, et al
.
2011
.
Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of th17 cell differentiation.
Cell Host Microbe
10
:
273
284
.
68
Wu
H. J.
,
Ivanov
I. I.
,
Darce
J.
,
Hattori
K.
,
Shima
T.
,
Umesaki
Y.
,
Littman
D. R.
,
Benoist
C.
,
Mathis
D.
.
2010
.
Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.
Immunity
32
:
815
827
.
69
Garrett
W. S.
,
Gallini
C. A.
,
Yatsunenko
T.
,
Michaud
M.
,
DuBois
A.
,
Delaney
M. L.
,
Punit
S.
,
Karlsson
M.
,
Bry
L.
,
Glickman
J. N.
, et al
.
2010
.
Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis.
Cell Host Microbe
8
:
292
300
.
70
Stepankova
R.
,
Powrie
F.
,
Kofronova
O.
,
Kozakova
H.
,
Hudcovic
T.
,
Hrncir
T.
,
Uhlig
H.
,
Read
S.
,
Rehakova
Z.
,
Benada
O.
, et al
.
2007
.
Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells.
Inflamm. Bowel Dis.
13
:
1202
1211
.
71
Kriegel
M. A.
,
Sefik
E.
,
Hill
J. A.
,
Wu
H. J.
,
Benoist
C.
,
Mathis
D.
.
2011
.
Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice.
Proc. Natl. Acad. Sci. USA
108
:
11548
11553
.
72
Lee
Y. K.
,
Menezes
J. S.
,
Umesaki
Y.
,
Mazmanian
S. K.
.
2011
.
Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis.
Proc. Natl. Acad. Sci. USA
108
(
Suppl. 1
):
4615
4622
.
73
Kinnebrew
M. A.
,
Buffie
C. G.
,
Diehl
G. E.
,
Zenewicz
L. A.
,
Leiner
I.
,
Hohl
T. M.
,
Flavell
R. A.
,
Littman
D. R.
,
Pamer
E. G.
.
2012
.
Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense.
Immunity
36
:
276
287
.
74
Lee
S. J.
,
McLachlan
J. B.
,
Kurtz
J. R.
,
Fan
D.
,
Winter
S. E.
,
Baumler
A. J.
,
Jenkins
M. K.
,
McSorley
S. J.
.
2012
.
Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development.
PLoS Pathog.
8
:
e1002499
.
75
Shaw
M. H.
,
Kamada
N.
,
Kim
Y. G.
,
Núñez
G.
.
2012
.
Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine.
J. Exp. Med.
209
:
251
258
.
76
Bettelli
E.
,
Carrier
Y.
,
Gao
W.
,
Korn
T.
,
Strom
T. B.
,
Oukka
M.
,
Weiner
H. L.
,
Kuchroo
V. K.
.
2006
.
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
Nature
441
:
235
238
.
77
Veldhoen
M.
,
Hocking
R. J.
,
Atkins
C. J.
,
Locksley
R. M.
,
Stockinger
B.
.
2006
.
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
Immunity
24
:
179
189
.
78
Zielinski
C. E.
,
Mele
F.
,
Aschenbrenner
D.
,
Jarrossay
D.
,
Ronchi
F.
,
Gattorno
M.
,
Monticelli
S.
,
Lanzavecchia
A.
,
Sallusto
F.
.
2012
.
Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β.
Nature
484
:
514
518
.
79
Lupp
C.
,
Robertson
M. L.
,
Wickham
M. E.
,
Sekirov
I.
,
Champion
O. L.
,
Gaynor
E. C.
,
Finlay
B. B.
.
2007
.
Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae.
Cell Host Microbe
2
:
204
.
80
Stecher
B.
,
Robbiani
R.
,
Walker
A. W.
,
Westendorf
A. M.
,
Barthel
M.
,
Kremer
M.
,
Chaffron
S.
,
Macpherson
A. J.
,
Buer
J.
,
Parkhill
J.
, et al
.
2007
.
Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.
PLoS Biol.
5
:
2177
2189
.
81
Gaffen
S. L.
2011
.
Recent advances in the IL-17 cytokine family.
Curr. Opin. Immunol.
23
:
613
619
.
82
Huang
W.
,
Na
L.
,
Fidel
P. L.
,
Schwarzenberger
P.
.
2004
.
Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.
J. Infect. Dis.
190
:
624
631
.
83
Saijo
S.
,
Ikeda
S.
,
Yamabe
K.
,
Kakuta
S.
,
Ishigame
H.
,
Akitsu
A.
,
Fujikado
N.
,
Kusaka
T.
,
Kubo
S.
,
Chung
S. H.
, et al
.
2010
.
Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans.
Immunity
32
:
681
691
.
84
Conti
H. R.
,
Shen
F.
,
Nayyar
N.
,
Stocum
E.
,
Sun
J. N.
,
Lindemann
M. J.
,
Ho
A. W.
,
Hai
J. H.
,
Yu
J. J.
,
Jung
J. W.
, et al
.
2009
.
Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis.
J. Exp. Med.
206
:
299
311
.
85
Ho
A. W.
,
Shen
F.
,
Conti
H. R.
,
Patel
N.
,
Childs
E. E.
,
Peterson
A. C.
,
Hernández-Santos
N.
,
Kolls
J. K.
,
Kane
L. P.
,
Ouyang
W.
,
Gaffen
S. L.
.
2010
.
IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail.
J. Immunol.
185
:
1063
1070
.
86
Kagami
S.
,
Rizzo
H. L.
,
Kurtz
S. E.
,
Miller
L. S.
,
Blauvelt
A.
.
2010
.
IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans.
J. Immunol.
185
:
5453
5462
.
87
Puel
A.
,
Picard
C.
,
Cypowyj
S.
,
Lilic
D.
,
Abel
L.
,
Casanova
J. L.
.
2010
.
Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?
Curr. Opin. Immunol.
22
:
467
474
.
88
Puel
A.
,
Cypowyj
S.
,
Bustamante
J.
,
Wright
J. F.
,
Liu
L.
,
Lim
H. K.
,
Migaud
M.
,
Israel
L.
,
Chrabieh
M.
,
Audry
M.
, et al
.
2011
.
Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.
Science
332
:
65
68
.
89
Liu
L.
,
Okada
S.
,
Kong
X. F.
,
Kreins
A. Y.
,
Cypowyj
S.
,
Abhyankar
A.
,
Toubiana
J.
,
Itan
Y.
,
Audry
M.
,
Nitschke
P.
, et al
.
2011
.
Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.
J. Exp. Med.
208
:
1635
1648
.
90
Ye
P.
,
Rodriguez
F. H.
,
Kanaly
S.
,
Stocking
K. L.
,
Schurr
J.
,
Schwarzenberger
P.
,
Oliver
P.
,
Huang
W.
,
Zhang
P.
,
Zhang
J.
, et al
.
2001
.
Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.
J. Exp. Med.
194
:
519
527
.
91
Griffin
A. J.
,
McSorley
S. J.
.
2011
.
Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda.
Mucosal Immunol.
4
:
371
382
.
92
Ravindran
R.
,
Foley
J.
,
Stoklasek
T.
,
Glimcher
L. H.
,
McSorley
S. J.
.
2005
.
Expression of T-bet by CD4 T cells is essential for resistance to Salmonella infection.
J. Immunol.
175
:
4603
4610
.
93
VanCott
J. L.
,
Chatfield
S. N.
,
Roberts
M.
,
Hone
D. M.
,
Hohmann
E. L.
,
Pascual
D. W.
,
Yamamoto
M.
,
Kiyono
H.
,
McGhee
J. R.
.
1998
.
Regulation of host immune responses by modification of Salmonella virulence genes.
Nat. Med.
4
:
1247
1252
.
94
Schulz
S. M.
,
Köhler
G.
,
Holscher
C.
,
Iwakura
Y.
,
Alber
G.
.
2008
.
IL-17A is produced by Th17, gammadelta T cells and other CD4− lymphocytes during infection with Salmonella enterica serovar Enteritidis and has a mild effect in bacterial clearance.
Int. Immunol.
20
:
1129
1138
.
95
Schulz
S. M.
,
Köhler
G.
,
Schütze
N.
,
Knauer
J.
,
Straubinger
R. K.
,
Chackerian
A. A.
,
Witte
E.
,
Wolk
K.
,
Sabat
R.
,
Iwakura
Y.
, et al
.
2008
.
Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17.
J. Immunol.
181
:
7891
7901
.
96
Godinez
I.
,
Keestra
A. M.
,
Spees
A.
,
Bäumler
A. J.
.
2011
.
The IL-23 axis in Salmonella gastroenteritis.
Cell. Microbiol.
13
:
1639
1647
.
97
Raffatellu
M.
,
Santos
R. L.
,
Verhoeven
D. E.
,
George
M. D.
,
Wilson
R. P.
,
Winter
S. E.
,
Godinez
I.
,
Sankaran
S.
,
Paixao
T. A.
,
Gordon
M. A.
, et al
.
2008
.
Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut.
Nat. Med.
14
:
421
428
.
98
Gordon
M. A.
2008
.
Salmonella infections in immunocompromised adults.
J. Infect.
56
:
413
422
.
99
Keestra
A. M.
,
Godinez
I.
,
Xavier
M. N.
,
Winter
M. G.
,
Winter
S. E.
,
Tsolis
R. M.
,
Bäumler
A. J.
.
2011
.
Early MyD88-dependent induction of interleukin-17A expression during Salmonella colitis.
Infect. Immun.
79
:
3131
3140
.
100
Geddes
K.
,
Rubino
S. J.
,
Magalhaes
J. G.
,
Streutker
C.
,
Le Bourhis
L.
,
Cho
J. H.
,
Robertson
S. J.
,
Kim
C. J.
,
Kaul
R.
,
Philpott
D. J.
,
Girardin
S. E.
.
2011
.
Identification of an innate T helper type 17 response to intestinal bacterial pathogens.
Nat. Med.
17
:
837
844
.
101
Siegemund
S.
,
Schütze
N.
,
Schulz
S.
,
Wolk
K.
,
Nasilowska
K.
,
Straubinger
R. K.
,
Sabat
R.
,
Alber
G.
.
2009
.
Differential IL-23 requirement for IL-22 and IL-17A production during innate immunity against Salmonella enterica serovar Enteritidis.
Int. Immunol.
21
:
555
565
.
102
Srinivasan
A.
,
Salazar-Gonzalez
R. M.
,
Jarcho
M.
,
Sandau
M. M.
,
Lefrancois
L.
,
McSorley
S. J.
.
2007
.
Innate immune activation of CD4 T cells in salmonella-infected mice is dependent on IL-18.
J. Immunol.
178
:
6342
6349
.
103
Kupz
A.
,
Guarda
G.
,
Gebhardt
T.
,
Sander
L. E.
,
Short
K. R.
,
Diavatopoulos
D. A.
,
Wijburg
O. L.
,
Cao
H.
,
Waithman
J. C.
,
Chen
W.
, et al
.
2012
.
NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells.
Nat. Immunol.
13
:
162
169
.
104
Siegemund
S.
,
Schütze
N.
,
Freudenberg
M. A.
,
Lutz
M. B.
,
Straubinger
R. K.
,
Alber
G.
.
2007
.
Production of IL-12, IL-23 and IL-27p28 by bone marrow-derived conventional dendritic cells rather than macrophages after LPS/TLR4-dependent induction by Salmonella enteritidis.
Immunobiology
212
:
739
750
.
105
Perona-Wright
G.
,
Jenkins
S. J.
,
O’Connor
R. A.
,
Zienkiewicz
D.
,
McSorley
H. J.
,
Maizels
R. M.
,
Anderton
S. M.
,
MacDonald
A. S.
.
2009
.
A pivotal role for CD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivo.
J. Immunol.
182
:
2808
2815
.
106
Barr
T. A.
,
Brown
S.
,
Mastroeni
P.
,
Gray
D.
.
2010
.
TLR and B cell receptor signals to B cells differentially program primary and memory Th1 responses to Salmonella enterica.
J. Immunol.
185
:
2783
2789
.
107
Salazar-Gonzalez
R. M.
,
McSorley
S. J.
.
2005
.
Salmonella flagellin, a microbial target of the innate and adaptive immune system.
Immunol. Lett.
101
:
117
122
.
108
Mizel
S. B.
,
Bates
J. T.
.
2010
.
Flagellin as an adjuvant: cellular mechanisms and potential.
J. Immunol.
185
:
5677
5682
.
109
Raffatellu
M.
,
George
M. D.
,
Akiyama
Y.
,
Hornsby
M. J.
,
Nuccio
S. P.
,
Paixao
T. A.
,
Butler
B. P.
,
Chu
H.
,
Santos
R. L.
,
Berger
T.
, et al
.
2009
.
Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine.
Cell Host Microbe
5
:
476
486
.
110
Blaschitz
C.
,
Raffatellu
M.
.
2010
.
Th17 cytokines and the gut mucosal barrier.
J. Clin. Immunol.
30
:
196
203
.
111
Salazar-Gonzalez
R. M.
,
Niess
J. H.
,
Zammit
D. J.
,
Ravindran
R.
,
Srinivasan
A.
,
Maxwell
J. R.
,
Stoklasek
T.
,
Yadav
R.
,
Williams
I. R.
,
Gu
X.
, et al
.
2006
.
CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches.
Immunity
24
:
623
632
.
112
Santos
R. L.
,
Raffatellu
M.
,
Bevins
C. L.
,
Adams
L. G.
,
Tükel
C.
,
Tsolis
R. M.
,
Bäumler
A. J.
.
2009
.
Life in the inflamed intestine, Salmonella style.
Trends Microbiol.
17
:
498
506
.

The authors have no financial conflicts of interest.