Development and Survival of Th17 Cells within the Intestines: The Influence of Microbiome- and Diet-Derived Signals

This information is current as Joseph H. Chewning and Casey T. Weaver of September 26, 2021. J Immunol 2014; 193:4769-4777; ; doi: 10.4049/jimmunol.1401835 http://www.jimmunol.org/content/193/10/4769 Downloaded from

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Development and Survival of Th17 Cells within the Intestines: The Influence of Microbiome- and Diet-Derived Signals Joseph H. Chewning* and Casey T. Weaver† Th17 cells have emerged as important mediators of host is achieved, at least in in part, through the dual role of TGF-b defense and at barrier sites, particularly the in promoting developmental pathways of both of these im- intestines, where the greatest number and diversity of portant subsets. the microbiota reside. A critical balance exists between TGF-b signaling induces the expression of both FoxP3 and protection of the host from its own microbiota and RORgt in Ag-stimulated naive T cells through a SMAD- dependent mechanism (reviewed in Ref. 10). Interestingly, pathogens and the development of immune-mediated Downloaded from disease. Breaches of local innate immune defenses pro- FoxP3 acts to inhibit RORgt through a direct protein–pro- vide critical stimuli for the induction of Th17 cell de- tein interaction, while also suppressing Il17a transcription velopment, and additional cues within these tissues through a DNA-binding mechanism (11, 12). High con- promote Th17 cell survival and/or plasticity. Normally, centrations of TGF-b result in increased levels of FoxP3 and this results in eradication of the microbial threat subsequent induction of Tregs that develop in the periphery. In contrast, lower concentrations of TGF-b are capable of and restitution of homeostasis. When dysregulated, http://www.jimmunol.org/ synergizing with inflammatory (e.g., IL-6 and IL-1) however, Th17 cells can cause a range of immune- to induce the development of Th17 cells (11). Thus, although mediated diseases, whether directed against Ags derived high TGF-b levels act to suppress Th17 development, lower from the microbiota, such as in inflammatory bowel dis- levels coupled with other inflammatory signals promote the ease, or against self-Ags in a range of autoimmune dis- Th17 lineage. Through mechanisms that are yet to be fully eases. This review highlights recent discoveries that defined, inflammatory cytokines are also able to reverse the provide new insights into ways in which environmental FoxP3-mediated suppression of RORgt in established pTregs, signals impact Th17 cell development and function in providing a mechanism for Treg plasticity in the setting of the intestines. The Journal of Immunology, 2014, infection (12). Therefore, the balance between pro- and anti- by guest on September 26, 2021 193: 4769–4777. inflammatory responses in the gastrointestinal (GI) tract is based, in part, on local levels of TGF-b and other cytokines, as well as other stimuli generated by the microbiota or the ransforming growth factor-b performs a critical role immune response to this flora (13). This balance affects local in the extrathymic generation of “peripheral” regu- immune regulation in the gut and was shown to have global latory T cells (pTregs; to be distinguished from T effects on the immune system and host health (14–19). “thymic” regulatory T cells [Tregs]) (1, 2), and the absence of Recent discoveries have further elucidated the relationship b + TGF- results in decreased FoxP3 T cells, which is associ- between the immune system and the microbiota and the mech- ated with severe autoimmune disease (3, 4). Based on the anisms for the generation of Th17 cells within the intestines immune-suppressive role of this , the discovery that (9, 20). The gastrointestinal tract represents the largest organ TGF-b is also important for the development of proin- of the immune system. Within the intestinal tract, ∼100 flammatory Th17 cells seemed contradictory (5–8). However, trillion organisms make up the microbiome, residing in maintenance of the equilibrium between the immune system symbiosis with the host (21). The host immune system and the and the intestinal microbiota has proved to reflect a balance intestinal microbiota interact continuously following coloni- between the effects of Tregs to repress inflammation directed zation of the intestines over the first few days of life. A major against normal constituents of the microbiome and that of function of the host immune system is to restrain inflamma- Th17 cells to mount inflammatory responses that clear tory responses to normal constituents of the microbiota while organisms that traverse the intestinal barrier (9). This balance retaining the capability to mount vigorous responses against

*Department of Pediatrics, Pediatric Blood and Marrow Transplantation Program, Uni- cephalitis; ENTPDase, ectonucleoside triphosphate diphosphohydrolase; GI, gastroin- versity of Alabama at Birmingham, Birmingham, AL 35294; and †Department of Pa- testinal; HIF-1, hypoxia-inducible factor 1; IBD, inflammatory bowel disease; IEC, thology, University of Alabama at Birmingham, Birmingham, AL 35294 intestinal epithelial cell; LP, ; MLN, mesenteric lymph node; PRR, pat- tern recognition receptor; pTreg, peripheral ; SCFA, short-chain fatty Received for publication August 11, 2014. Accepted for publication August 25, 2014. acid; SFB, segmented filamentous bacteria; SILP, small intestine LP; Treg, regulatory Address correspondence and reprint requests to Dr. Joseph H. Chewning, Department T cell; UC, ulcerative colitis. of Pediatrics, University of Alabama at Birmingham, 845 Nineteenth Street South, Birmingham, AL 35294-2170. E-mail address: [email protected] Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Abbreviations used in this article: Ahr, aryl hydrocarbon receptor; CD, Crohn’s disease; DC, ; DSS, dextran sulfate sodium; EAE, experimental autoimmune en-

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401835 4770 BRIEF REVIEWS: Th17 DEVELOPMENT potential pathogens, whether they derive from the resident ingly, presentation of SFB Ags appears to occur within the LP, microbiota or result from infection. not in secondary lymph tissues, and requires MHC class II on Dendritic cells (DCs) are a critical component in the in- CD11c+ APCs (38). Colonization with SFB also induces teraction between the immune system and the microbiota, and a nonspecific Th17 response that occurs in the absence of or- they act to bridge the innate and adaptive immune responses. ganized lymph tissues (40). Other types of bacteria were shown Within the intestinal mucosa, DCs are grouped based on the to preferentially induce Treg responses in the intestines. Col- expression of CD103 (integrin aE) and CD11b, with num- onization with certain Clostridium species (specifically clusters bers of each subset varying according to differing segments of IV, XIVa, and XVIII), spore-forming members of the normal the GI tract (22–25). CD103+ DCs reside primarily within microbiota, increased TGF-b secretion by intestinal epithelial the lamina propria (LP), with low numbers contained in the cells (IECs) through a PRR-independent mechanism (41, 42). epithelium, where they can migrate along the basement Recently, another member of the TGF-b family, TGF-b3, membrane. Recent studies indicate that these cells can project was proposed to induce a more pathogenic Th17 cell capable of intraepithelial dendrites into the intestinal lumen that act to inducing increased severity of experimental autoimmune en- phagocytose bacteria and, somewhat less efficiently, sample cephalitis (EAE) in mice (43). TGF-b3 is normally produced luminal Ag (26). Following encounter with pathogenic bac- by endothelium and other sources (including Th17 cells) and is teria (e.g., Salmonella), additional CD103+ DCs are recruited present in normal plasma (44). Both TGF-b1 and TGF-b3 from the LP in a TLR- and -dependent manner form a ternary complex with type I and II receptors (TbRI and

(26). Additional data indicate that luminal Ags also may be TbRII, respectively), but with differing affinity (45), and it is Downloaded from passed to underlying CD103+ DCs via goblet cells (27). After possible that differential binding to TGF-bR by TGF-b3 plays antigenic challenge, DCs upregulate CCR7 and migrate to a role in altered T cell differentiation. It is unclear how much mesenteric lymph nodes (MLNs) (28–30), where they present TGF-b3 is normally present in the intestinal mucosa and what Ag and initiate the adaptive immune response (30–33). role the microbiota might have in altering TGF-b3 levels. The presentation by DCs of Ags derived from the microbiota Despite the relatively early discovery of the importance of or pathogens initiates the development of effector T cells. TGF-b and IL-6 in Th17 development, much remains un- http://www.jimmunol.org/ Lineage-specifying signals are transmitted to naive T cells along known regarding the mechanisms controlling production of with Ag by DCs, contingent on their activation by TLRs and these cytokines and the impact that the balance of cytokine- other pattern recognition receptor (PRR) pathways (34). Other induced signals (TGF-b, IL-6 and others) has on maintaining signals also provide critical stimuli for determining mature immune homeostasis within the intestinal mucosa. Further T cell fate within the MLNs. CD103+ DCs present in the details also remain to be elucidated regarding the influence of MLNs were initially demonstrated to promote pTreg devel- the microbiome on TGF-b, IL-6, and other critical cytokines opment via increased TGF-b secretion and retinoic acid (31), that impact the development of Th17 cells and Tregs within the 2 whereas the CD103 DCs were responsible for producing in- GI tract. by guest on September 26, 2021 flammatory signals. Further studies demonstrated that the 2 CD103+CD11b+ and CD103+CD11b DC subsets promote IL-23 signaling is critical for both Th17 cell survival and plasticity different mature T cell lineages (23). These studies revealed that 2 IL-23 is a heterodimeric protein consisting of the unique p19 the CD103+CD11b+ subset, as well as the CD103 subset, was subunit and the p40 subunit, which is shared with IL-12 (which capable of promoting Th17 development, primarily through consists of the p40 and p35 proteins). Prior to the identification secretion of IL-6 (35). Thus, evidence indicates that the balance of IL-23, experimental colitis models were thought to be sec- of pro- and anti-inflammatory signals is dependent, at least in ondary to IL-12 signaling, resulting in enhanced Th1 devel- part, on the nature of the cell presenting intestinal Ags to T cells opment. Subsequent studies identified IL-23 as a unique within the MLN. cytokine and found that it has an indispensable role in mediating Additional studies revealed other mechanisms for regulating autoimmune disease (46, 47). IL-23 also provides critical de- the immune balance in the intestinal tract. Phagocytosis of velopmental and survival signals for Th17 cells. apoptotic cells by host DCs results in the production of TGF-b, TGF-b and IL-6 promote the development of Th17 cells which can promote pTreg development. However, ingestion of from naive CD4+ T cells and induce upregulation of IL-23R. infected apoptotic cells results in the additional secretion of IL-6 IL-23 signaling acts to further upregulate IL-23R expression (in a TLR-dependent manner), which alternatively promotes (48). Although IL-23 is not required for the initial differen- the development of Th17 cells (36). Specific microorganisms tiation of Th17 cells, the absence of IL-23 signals results in also were shown to induce the development of Th17 cells abbreviated Th17 maturation and decreased Th17 prolifera- through similar mechanisms. It was demonstrated that intes- tion (49). The generation of Th17 memory cells and the tinal colonization with a single bacterial strain, so-called “seg- generation of secondary recall responses also appear to be mented filamentous bacteria” (SFB), is capable of inducing critically dependent on IL-23 signaling (50). The absence of Th17 development in the intestines. SFB colonization of the IL-23 signals results in reduced Th17 production of GM-CSF ileum, and Peyer’s patches in particular, upregulates expression and IL-22, two critical cytokines in Th17-mediated host of serum amyloid A, which is capable of inducing increased IL-6 protection and inflammation (51, 52). and IL-23 secretion by LP DCs (37). Th17 cells present within Th17 cells have a high propensity for developmental flex- the small intestine LP (SILP) recognize and respond to SFB Ags, ibility (or “plasticity”), including the upregulation of IFN-g whereas these same Ags do not induce cytokine production production (53–55). Following acquisition of IFN-g, these from non-Th17 cells (38, 39). SILP Th17 cells possess a distinct Th17 cells either become IL-17–IFN-g dual producers or can TCR repertoire, enriched for Vb14, which is capable of rec- downregulate RORgt and IL-17 (and other Th17 mediators) ognizing multiple SFB-encoded peptides (38, 39). Interest- and upregulate T-bet to become an IFN-g producer with The Journal of Immunology 4771 many features of Th1 cells (53–55). These converted Th17 acts to repress the p40 subunit of IL-12 and IL-23, and levels cells have been designated Th17/Th1 or Th1-like cells to of this miRNA were higher in germ-free mice. Restoration of discriminate them from de novo Th1 cells. We and others the normal gut flora resulted in decreased miR-10a and in- (53, 54) demonstrated an important role for IL-23 in the creased levels of IL-23. In addition, lower levels of miR-10a conversion of Th17 precursors to Th1-like cells, both in vitro were seen in IL-10–knockout colitis mice (64). Another and in vivo. Thus, IL-23 is an important cytokine in deter- microRNA, miR-107, also acts to control intestinal inflam- mining both the survival and ultimate developmental fate of mation by repressing IL-23p19 in the GI tract, particularly Th17 cells. within IECs and CD11c+ and DCs. Presence IL-23 in the GI tract is produced primarily by tissue-resident of the intestinal microbiota downregulates miR-107 levels 2 DCs and macrophages (56). In particular, CD103 DCs through a MyD88-dependent mechanism, resulting in in- within the GI tract were demonstrated to produce inflam- creased IL-23 levels (65). Another mechanism of microbiota- matory cytokines, and specifically IL-23 (31). Classically, induced regulation of IL-23 is through dietary metabolites CD103+ DCs have not been demonstrated to secrete signifi- produced by luminal bacteria. Butyrate is a short-chain fatty cant levels of IL-23, but instead they seem poised to promote acid (SCFA) produced by constituents of the microbiome. Treg development (see previous section). However, studies SCFAs are known to reduce inflammation in the GI tract (see showed that CD103+CD11b+ DCs are capable of inducing later section); however, high levels of oral butyrate increased Th17 cells (35). Recently, TLR5-expressing CD103+CD11b+ IL-23 secretion by DCs that resulted in increased Th17 cells

DCs were shown to produce increased IL-23 levels in re- (66). Further, in this model, increased butyrate exacerbated Downloaded from sponse to bacterial flagellin, which binds TLR5. The pro- dextran sulfate sodium (DSS)- induced colitis (66). duction of IL-23 by these cells further induces the production In addition to its role in modulating the host response to of IL-22 within the LP of exposed mice (57). Finally, LP the resident microbiota, IL-23 is critical to host defense CD11c+ DCs also were shown to secrete increased IL-23 against certain intestinal pathogens. Citrobacter rodentium upon coculture with serum amyloid A, a protein produced is a murine pathogen that normally induces a self-limiting by SFB (37). enteritis that mimics enteropathogenic Escherichia coli and http://www.jimmunol.org/ IL-23 was shown to be an important mediator of GI disease, enterohemorrhagic E. coli infection in humans. Infection by including inflammatory bowel disease (IBD) and intestinal C. rodentium induces increased IL-23 expression in the intestines graft versus host disease of the intestines (58–61). In murine of infected mice. Deficiency or neutralization of IL-23 renders models, IL-23 is critical for the development of severe disease the host lethally susceptible to C. rodentium colitis (7), largely in the CD4+CD45RBhi transfer colitis model (58). Blockade duetotheabsenceofIL-23–mediated IL-22 secretion, of IL-23 signaling in transferred T cells was associated with whether by innate lymphoid cells or CD4+ T cells (51, 67, decreased tissue levels of IFN-g and reduced pathology. IL-23 68). Similarly, Clostridium difficile is associated with elevated

signaling was associated with increased numbers and prolif- levels of IL-23 in human samples, as well as in mouse models by guest on September 26, 2021 eration of IL-17–IFN-g dual-positive cells, suggesting a criti- of the disease, although IL-23 neutralization in mice with cal role in the transition from Th17 to Th1-like cells (58). In C. difficile colitis ameliorated disease and reduced mortality (69). a TCR-transgenic colitis model, Th17 cells expressing the Similar to its effects in T cell models of colitis, IL-23 acts CBir1 TCR (specific for an immunodominant microbiota through both IL-17/Th17 and/or the IFN-g/Th1 (Th1-like) Ag) induced severe colitis, which was associated with in- pathways in infectious colitis models. Infection with enter- creased IFN-g and Th1-like cells present within diseased otoxigenic Bacteroides fragilis induces a severe colitis and tissue (62). Blockade of IL-17A reduced disease in these mice. inflammation-induced cancer in mice (70). The disease is Mechanistic studies revealed that Th17-produced IL-17 in- mediated by IL-23, and IL-23R blockade abrogates colitis and duced DC release of IL-23 and IL-12, which, in turn, pro- carcinogenesis. The inflammatory T cells present in LP pri- moted the transition from Th17 to Th1-like cells. marily produce IL-17, with only small amounts of IFN-g. Both ulcerative colitis (UC) and Crohn’s disease (CD) have Additionally, increased levels of IL-6, TGF-b, and IL-1b are been linked to IL-23 signaling, although CD has classically present in the inflamed tissues. Murine colitis due to Heli- been deemed a Th1-dependent disease, whereas UC has not. cobacter hepaticus infection also was demonstrated to be de- In studies using LP CD4+ T cells from patients with IBD, pendent on excess IL-23 levels (71). However, it was found both patient groups demonstrated increased expression of IL- that disease is associated with increased infiltrating CD4+ cells 23R on LP T cells. Further, CD4+ T cells from patients with that were primarily IFN-g secreting (either IL-17–IFN-g dual UC upregulated IL17A mRNA and secreted increased IL-17A positive or IFN-g single positive) (72). Moreover, when IL- in response to IL-23, whereas CD4+ T cells from patients with 17+ cells were harvested from colitic mice and transferred CD upregulated IFN-g (63). Whether these differential ef- to secondary hosts, disease was induced, and the transferred fects of IL-23 are a feature of all patients with UC or CD is cells progressively transitioned to Th1-like cells. Using fate- unknown, but they suggest a critical role for IL-23 in the reporter mice (55), it was demonstrated that the CD4+ T cells pathogenesis of both forms of IBD. progress through an early Th17 phase and ultimately develop The resident microbiota can contribute directly to local IL- into a Th1-like cell throughout the course of the infection 23 levels in the intestinal mucosa through several mechanisms. (72). Thus, IL-23 appears to primarily sustain Th17 responses Colonization with the normal flora was shown to increase IL- in some circumstances or facilitate the transition from a Th17 23 levels in the murine GI tract. Through a TLR-dependent to a dominant Th1-like response in others. mechanism, colonization with microbiota downregulated DC Although IL-23 has emerged as a central cytokine in Th17- expression of miR-10a, a microRNA that is expressed at in- mediated host protection and immune-mediated disease, its creased levels in the murine intestine (64). Normally, miR-10a precise function is incompletely understood. Similarly, the 4772 BRIEF REVIEWS: Th17 DEVELOPMENT relative importance of Th17-derived IL-17 and IFN-g single- peractive NLRP3 mutations demonstrate increased serum IL- positive cells, as well as IL-17–IFN-g dual-positive cells, in 17, as well as increased numbers of circulating Th17 cells. host protection and intestinal inflammation and tissue dam- DCs from these patients secrete increased levels of IL-1, and age has not been completely defined. Additionally, it is cur- treatment of these patients with anti–IL-1 therapy results in rently unknown how the balance between IL-23–driven Th17 resolution of these findings (85). versus Th1-like differentiation is controlled, although TGF- Recent studies highlighted the importance of IL-1b in b–mediated downmodulation of STAT4 activation down- maintaining Th17 development in the intestinal mucosa. In stream of IL-23 signaling and, thus, blunting of the transition CD4+CD45RBhi transfer colitis model studies, IL-1 was to a Th1-like program (53), might be contributory. Another demonstrated to be important for the development of disease important signal that may be quite influential in strengthen- and was associated with increased levels of IL-6 and IL-17, as ing IL-23–induced Th17 stability is the cytokine IL-1b. well as Th17 cell numbers. An absence of IL-1 signaling resulted in decreased Th17 survival, but not development, Role of IL-1b in stabilizing the Th17 phenotype within the intestinal mucosa that was associated with lower As detailed earlier in this review, TGF-b and IL-6 initially levels of antiapoptotic protein Bcl2 and Bclxl transcripts (76). were demonstrated to be important in Th17 development These studies indicated an essential role for IL-1 in facilitating from naive CD4 T cells in murine studies (5, 7). However, colitis through its promotion of Th17 cell survival and ac- early data in humans demonstrated an important role for cumulation within the intestines. IL-1b (IL-1), but not TGF-b, in promoting the Th17 lineage The intestinal microbiota also was shown to have a direct Downloaded from (73). Furthermore, studies in the Th17-mediated EAE mouse impact on Th17 development through the generation of IL- model also indicated that IL-1 signaling was important for 1b. The absence of IL-1 or IL-1R signaling in mice resulted + disease (74). The IL-1 receptor (IL-1R1) is upregulated in in decreased Th17 cells within the intestinal LP. CD11b developing Th17 cells, and its expression appears to be in- macrophages were identified as the source of intestinal IL-1 duced by IL-6 and IL-23 signaling (75, 76). IL-1 signaling secretion, and IL-1 production occurred in a MyD88- was shown to be important for promoting both Th17 de- dependent manner (86). Th17 cell development was depen- http://www.jimmunol.org/ velopment and maintenance (75). IL-1 synergizes with IL-6 to dent on T cell–specific IL-1 signaling. Interestingly, germ-free enhance expression of IRF4 and RORgt (75), both of which mice demonstrated recapitulation of the Th17 cell population are important transcription factors required for Th17 devel- following IL-1b treatment, indicating a critical role for opment (77, 78). IL-1 also acts to suppress TGF-b–mediated microbiota in regulating intestinal Th17 cells through the FoxP3 upregulation (79). In contrast, IL-1–induced Th17 induction of IL-1b production (86). proliferation appears to be mediated by the mTOR-signaling IL-1b also provides important signals for the maintenance pathway, and this can be inhibited by the SIGIRR receptor, of intestinal homeostasis and host–microbiota symbiosis. an important receptor for in the intestinal Absence of NLRP3 signaling (with concomitantly decreased by guest on September 26, 2021 mucosa (80). IL-1b) results in dysbiosis in mouse models, with increased Although many cells can produce IL-1, IL-1b is produced intestinal colonization of pathogenic species, including primarily by DCs and macrophages activated by microbe- Enterobacteriaceae, Mycobacterium,andClostridium (83). derived ligands for PRRs. For example, the NOD2 ligand Further, infection with C. difficile induces severe colitis, muramyldipeptide was demonstrated to induce DC produc- resulting in damage to the intestinal epithelial barrier. Altered tion of IL-1 and IL-23, with subsequent Th17 development intestinal epithelium was shown to be associated with trans- (81). Irrespective of the factor(s) that induces IL-1 expression, location of commensal bacteria, with subsequent IL-1 in- it is expressed as a propeptide that must be cleaved to become duction through an NLRP3-dependent process. Increased IL-1 active. The NLRP3 inflammasome is a key mediator of IL-1 acts in a feedback loop to promote clearance of C. difficile, cleavage in the intestines. It is made up of the NLRP3 and the absence of this cytokine results in increased suscep- member of the nucleotide-binding domain and leucine-rich tibility to infection and mortality (87). repeat–containing family of proteins. Following activation, Augmentation of intestinal Th17 is an important NLRP3 forms a complex with procaspase-1 and ASC, with role of IL-1b. It is not certain how this cytokine regulates the procaspase-1 subsequently undergoing cleavage and activa- development and/or survival of Th17 cells within the intes- tion. Active caspase-1 then cleaves pro–IL-1b and pro–IL-18 tines, but decreased or absent IL-1b signals result in lower precursors to the active forms of these cytokines. Th17 cell numbers within the GI tract. Additionally, human The absence of NLRP3 results in increased susceptibility to data implicate increased levels of this cytokine in Th17- experimental colitis in murine models (82, 83). This is due to mediated inflammation and disease. decreased levels of both IL-1b and IL-18, which results in increased intestinal epithelial permeability and decreased Importance of aryl hydrocarbon receptor ligands and ATP produced by production of b-defensins (82, 83). In contrast, hyperactive microbiota in Th17 development and survival NLRP3 mutations result in increased IL-1b levels, with The symbiotic relationship between the host and its intestinal concomitantly increased Th17 development in mice and microbiota is a multifaceted one, and we are only beginning to humans (84, 85). Mice with a hyperactivating NLRP3 mu- understand the factors that maintain this relationship. It is clear tation demonstrate increased levels of IL-1, numbers of Th17 that one beneficial role for the intestinal microbiota is the cells, and tissue levels of Th17-associated cytokines. Coculture production of important nondietary factors (e.g., vitamins) of CD11b+ DCs from NLRP3 mutant mice with wild-type that the host is incapable of synthesizing or metabolizing. CD4+ T cells resulted in increased IL-1–dependent Th17 Other factors, such as ligands of the aryl hydrocarbon receptor development (84). Furthermore, patients with various hy- (Ahr) or ATP, are derived from the diet and/or produced by The Journal of Immunology 4773 the microbiota and can directly affect mucosal immunity and, the immunologic response to the microbiota. Elegant studies specifically, Th17 development. demonstrated that Lactobacillus reuteri metabolizes trypto- Ahr is a member of the basic helix–loop–helix Per/Arnt/Sim phan through the enzyme aromatic amino acid aminotrans- (bHLH/PAS) receptor family; it resides in the cytosol in ferase to produce a potent Ahr ligand, indole-3-aldehyde, a complex with protein chaperones (e.g., Hsp90) where it which signals through Ahr to induce increased IL-17 and encounters and binds a variety of ligands, including xenobi- IL-22 levels within GI tissues of colonized mice (105). In the otic and naturally arising toxins. After ligand binding, the Ahr absence of IDO1, an important enzyme responsible for deg- complex translocates to the nucleus where it forms hetero- radation of tryptophan into immunologically active metabo- dimers with other member of the bHLH/PAS receptor family lites, mice demonstrated increased gastric colonization with and acts to control the transcription of multiple genes through L. reuteri, resulting in a compensatory increase in IL-22 Ahr-responsive elements (88). production that provided host resistance to Candida albicans Initial studies revealed that Th17 cells express Ahr, and that and ameliorated DSS-induced inflammation (105). Another an Ahr ligand, the photosynthesized tryptophan metabolite member of the Lactobacillus family, L. bulgaricus OLL1181 6-formylindolo [3,2-b] carbazole, augments Th17 development (L. helviticus), also was shown to activate Ahr signaling (89, 90). T cells derived from mice lacking Ahr demonstrated through a distinct, unknown mechanism (106). Other con- reduced upregulation of IL-17 and IL-22 under Th17- stituents of the resident microbiota (such as Clostridium promoting conditions in vitro, as well as reduced severity of sporogenes) have the ability to produce tryptophan derivatives

Th17-mediated disease (89, 91). In a collagen-induced ar- that bind and activate Ahr (107). Downloaded from thritis model, Ahr signaling was shown to be critical for in- The microbiota also produce ATP, a vital energy source that creasing Th17 cell numbers and disease severity (92). This enables innumerable cell functions. ATP secretion by multiple might be due, at least in part, to altered Th17 survival, be- intestinal bacteria was demonstrated, and it occurs via a gly- cause studies demonstrated that the absence of Ahr signaling colytic process that is dependent on luminal glucose levels results in decreased levels of antiapoptotic genes, such as Bcl2 (108, 109). ATP within the gut lumen can increase Th17 cell and Bcl2l1 (93). A contributor to Ahr-dependent upregula- numbers in the colonic LP (110). It was found that ATP http://www.jimmunol.org/ tion of IL-17 is the miR-132/212 cluster, and the absence of produced by the microbiota binds to purinergic receptors miR-132/212 resulted in decreased Th17-dependent CNS expressed on LP DCs (specifically the CD70hiCD11clo pop- inflammation in an EAE model (94). However, Ahr signaling ulation) to enhance production of IL-6, TGF-b, and IL-23 in through miR-132/212 did not influence IL-22 levels (94). a TLR-independent fashion. These DCs were capable of More recently, however, Ahr-deficient mice were shown to promoting Th17 cell development in vitro, and the absence of have increased Th17 cell numbers within the peripheral blood resident microbiota and/or treatment with an ATP antagonist and GI tract, particularly the small intestine (95, 96). These resulted in markedly decreased colonic Th17 cell numbers

studies reveal that the absence of Ahr signaling in vivo results (110). DCs also were shown to produce increased IL-1b levels by guest on September 26, 2021 in increased intestinal colonization with SFB, secondary to following ATP binding, which could contribute to Th17 cell decreased Ahr-dependent production of IL-22, which results development (111). in increased Th17 cell numbers. Furthermore, the increased ATP-binding purinergic receptors are expressed by multiple levels of IL-17 single-positive cells and IL-17–IFN-g dual- cell types. Recent studies demonstrated that IECs also express positive cells resulted in increased intestinal pathology (96). these receptors and, upon binding microbiota-produced ATP, Consistent with these findings, Ahr-deficient mice were found IECs produce IL-6 and TGF-b and stimulate local DCs to to have increased levels of both TGF-b1 and TGF-b3 (97). produce additional IL-6 and TGF-b, as well as IL-23 (112). Collectively, these studies also highlight an important differ- Furthermore, T cells express purinergic receptors and were ential effect of Ahr signaling on Th17 cell development and shown to produce increased IL-17 levels after direct ATP survival compared with Th22 cells, which are markedly re- binding (111). duced in Ahr-deficient mice (67, 96). Levels of extracellular ATP are closely regulated by the host Regardless of the apparently discrepant findings with regard through the expression of a family of enzymes called ecto- to Ahr signaling and Th17 development, it is clear that a tightly nucleoside triphosphate diphosphohydrolases (ENTPDases). regulated balance exists among the microbiota, host diet, and The most extensively studied of this family, ENTPDase1 or the immune cells present in the intestinal mucosa. Ahr ligands CD39, has an important role in controlling inflammation and are derived from dietary and nondietary sources. Dietary Ahr (113, 114). The absence of this enzyme ligands are typically found within fruits and vegetables and increases susceptibility to colitis in mice, and human muta- include flavonoids, such as kaempferol and quercetin, and tions are associated with an increased risk for IBD (114). indole-3-carbinol (as well as others) derived primarily from ENTPDase7 is expressed on endothelial cells in the small cruciferous vegetables (98, 99). Other sources include curcumin intestine and metabolizes luminal ATP produced by the metabolites (contained in spices) and resveratrol (red wine) microbiota (115). An absence of ENTPDase7 resulted in (100, 101). Endogenous Ahr ligands (especially kynurenines) augmented Th17 cell numbers within the LP, which was as- also play a significant role in modulating host immunity and sociated with increased severity of EAE but resistance to were shown to be important in murine colitis and tumor C. rodentium infection (115). This study highlights the impor- models (102, 103). Recently, another endogenous Ahr ligand, tance of regulated balance within the intestinal mucosa. cinnabarinic acid, was shown to induce T cell expression of Heightened ATP levels resulting from increased bacterial IL-22 (104). colonization and/or infection are detected by the host, with The microbiota itself can produce Ahr ligands that are ca- a subsequent increase in Th17 development for host protec- pable of promoting a host immune response that, in turn, alters tion. However, important regulatory mechanisms are required 4774 BRIEF REVIEWS: Th17 DEVELOPMENT to degrade excess ATP to prevent unchecked Th17 responses how the apparent fixed Th17 phenotype alters the manifes- that result in enteritis and autoimmunity. tations of disease should be informative. In any case, these studies provide additional support for the importance of di- Other environmental and dietary effects on Th17 development etary factors in maintaining and/or altering mucosal immu- Constituents of the microbiota, particularly members of the nity within the intestinal tract and specifically address the role Bacteroidetes and Firmicutes phyla, are responsible for me- of the luminal environment in promoting host Th17 devel- tabolism of dietary fiber into SCFAs within the GI tract (42, opment and inducing inflammation and/or autoimmunity. 116). The most studied of the SCFAs are acetate, isovalerate, Recently, another environmental factor—oxygen tension, propionate, and butyrate. SCFAs provide an energy source to particularly hypoxia—was demonstrated to have an important colonic epithelial cells that is important for maintenance of role in modulating Th17 development. Oxygen levels de- , a healthy mucosa (117). Butyrate was specifically shown to crease throughout the GI tract, reaching levels 5 torr within maintain intestinal epithelial tight junctions and decrease the distal colon and rectum (129). Important initial studies bacterial translocation (118, 119). SCFAs also dampen the revealed that hypoxia-inducible factor 1 (HIF-1) is important intestinal immune response through increased production of for Th17 development and, in particular, for controlling the TGF-b (42) and through suppression of inflammatory cyto- balance of Th17 and Treg differentiation (130, 131). HIF-1 kines, including IL-6, IL-17, and IFN-g (120–122). Luminal is a heterodimer composed of the HIF-1a and HIF-1b sub- acetate was shown to bind to the GPR43 receptor expressed units. The HIF-1a subunit is oxygen sensitive, whereas by IECs and neutrophils, and it downregulates the inflam- HIF-1b is constitutively expressed. Upregulation of HIF-1a Downloaded from matory response in DSS-induced colitis (120). Butyrate and expression occurs in a STAT3-dependent manner, and HIF-1a propionate appear to be the most potent SCFAs in abrogating induces glycolysis pathways that are crucial for Th17 cell inflammatory signals within the intestinal mucosa (123). This differentiation (131). HIF-1a also influences the Th17–Treg appears to be secondary to their ability to inhibit histone developmental balance by activating RORgttranscription, deacetylase, resulting in increased H3 acetylation of the while complexing with FoxP3 protein and von Hippel– FoxP3 promoter and CNS1 enhancer, which enhances Foxp3 Lindau protein to target both proteins for proteosomal http://www.jimmunol.org/ expression, but also through acetylation and stabilization of degradation (130). Recently, the microRNA miR-210 was FoxP3 protein itself (124, 125). In addition, butyrate expo- demonstrated to have an important role in regulating Th17 sure resulted in increased DC-mediated Treg development. development under hypoxic conditions. TCR stimulation This effect is likely due to repression of proinflammatory under hypoxic conditions induces HIF-1a, which increases genes, including Il12, Il6, and Relb, in butyrate-exposed the expression of miR-210 in a PI3K pathway–dependent DCs (124). manner. Subsequently, miR-210 acts in a negative-feedback SCFAs are critical regulators of the Th17 response and are loop to decrease Hif1a gene expression (132). Thus, aerobic/ the subject of ongoing research in the pathogenesis and anaerobic conditions within the GI tract, which are regulated, by guest on September 26, 2021 treatment of IBD and dysbiosis. Additionally, other dietary in part, by the microbiota, also influence the development of substances can induce IL-23 secretion and potentially alter the Th17 cells. Th17 balance within the intestines. These “food-derived bioactives” exhibit the ability to upregulate IL-23R expres- Conclusions It has been speculated that Th17 cells are the most primitive sion and Th17-associated cytokines in various cell lines, + mostly through unknown mechanisms (126). of the effector CD4 T cell subsets in evolutionary terms Other local environmental signals can influence intestinal and that they emerged in parallel with pTregs to provide immunity. Recently, increased dietary sodium levels were vertebrates a means to harness the metabolic potential of shown to induce the development of pathogenic Th17 cells a diverse intestinal microbiota (133). As more has been and exacerbate autoimmunity (127, 128). Human and murine learned regarding the special interplay between these naive CD4+ cells exposed to physiologically relevant increased barrier and the microbiota, this possibility sodium concentrations produced more IL-17 and other seems all the more compelling. Nowhere is the need to Th17-associated cytokines (e.g., GM-CSF) when stimulated finely balance immune tolerance and clearance mechanisms in vitro under Th17-promoting conditions (128). In vivo so critical as in the intestinal tract, where the greatest studies revealed that mice fed a high-sodium diet developed concentration and diversity of Ags, microbial and ingested, worsened manifestations of EAE. These effects were mediated are in intimate contact with the greatest number of innate by an NFAT5- and SGK1-dependent mechanism (128). and adaptive immune cells throughout life. Moreover, as it Notably, SGK1 levels are initially induced by TGF-b, but has become appreciated that the intestinal microbiota is stable expression is mediated by IL-23 signaling (127). Fur- a latent threat to promote Th17-mediated disease that thermore, SGK1 increases IL-23R expression, thereby estab- extends well beyond the intestines, the urgency to better lishing a positive-feedback mechanism by which heightened understand the factors that regulate Th17 and pTreg bi- sodium promotes heightened IL-23 signaling in Th17 cells. ology in the gut has grown. In view of the remarkable Surprisingly, increased sodium did not result in increased advances that have been made in the decade since the dis- IFN-g levels, despite upregulation of T-bet (127, 128). Al- covery of Th17 cells, the prospects for new understanding though the mechanism underlying this observation is unclear, that informs better therapies for immune-mediated disease it appears that heightened sodium exposure can increase Th17 driven by the Th17 pathway appear great. cell proliferation and survival while preventing Th1-like conversion. Future studies that explore the role of sustained Disclosures dietary sodium levels on development of autoimmunity and The authors have no financial conflicts of interest. The Journal of Immunology 4775

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