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Microbiome- and Diet-Derived Signals Within 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 References This article cites 133 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/193/10/4769.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology 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 homeostasis at barrier sites, particularly the in promoting developmental pathways of both of these im- intestines, where the greatest number and diversity of portant T cell 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 cytokines (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 cytokine, 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, lamina propria; MLN, mesenteric lymph node; PRR, pat- tern recognition receptor; pTreg, peripheral regulatory T cell; 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, dendritic cell; 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 chemokine-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.
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