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      The Intestine Harbors Functionally Distinct Homeostatic Tissue-Resident and Inflammatory Th17 Cells

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          Summary

          T helper 17 (Th17) cells are pathogenic in many inflammatory diseases, but also support the integrity of the intestinal barrier in a non-inflammatory manner. It is unclear what distinguishes inflammatory Th17 cells elicited by pathogens and tissue-resident homeostatic Th17 cells elicited by commensals. Here, we compared the characteristics of Th17 cells differentiating in response to commensal bacteria (SFB) to those differentiating in response to a pathogen ( Citrobacter rodentium). Homeostatic Th17 cells exhibited little plasticity towards expression of inflammatory cytokines, were characterized by a metabolism typical of quiescent or memory T cells, and did not participate in inflammatory processes. In contrast, infection-induced Th17 cells showed extensive plasticity towards pro-inflammatory cytokines, disseminated widely into the periphery, and engaged aerobic glycolysis in addition to oxidative phosphorylation typical for inflammatory effector cells. These findings will help ensure that future therapies directed against inflammatory Th17 cells do not inadvertently damage the resident gut population.

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          Highlights

          • •

            Tissue-resident, SFB-elicited Th17 cells are non-inflammatory

          • •

            Citrobacter-elicited Th17 cells show high plasticity towards inflammatory cytokines

          • •

            SFB Th17 cells are metabolically similar to resting memory cells

          • •

            Citrobacter Th17 cells are highly glycolytic effector cells

          Abstract

          The distinctions between inflammatory Th17 cells elicited by pathogens and tissue-resident homeostatic Th17 cells elicited by commensals are unclear. Omenetti et al. show that tissue-resident Th17 cells, in contrast to pathogen-elicited Th17 cells, exhibit little plasticity towards inflammatory cytokines, show muted metabolism, and do not participate in inflammatory reactions. These findings highlight the link between metabolic fitness and functional state.

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          Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.

          Daniel Cua, Jonathan P Sherlock, Yi. Chen … (2003)
          Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
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            Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.

            Hsin-Jung J. Wu, Ivaylo Ivanov, Jaime Darce … (2010)
            Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease. Copyright 2010 Elsevier Inc. All rights reserved.
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              Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

              Kamran Ghoreschi, Arian Laurence, Xiang-Ping Yang … (2010)
              CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity 1–4 . Crucial for T helper17 (Th17) cells in vivo 5,6 , IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification 7–10 . Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest an alternative mode for Th17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.
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                Author and article information

                Contributors
                Brigitta Stockinger
                Journal
                Journal ID (nlm-ta): Immunity
                Journal ID (iso-abbrev): Immunity
                Title: Immunity
                Publisher: Cell Press
                ISSN (Print): 1074-7613
                ISSN (Electronic): 1097-4180
                Publication date PMC-release: 16 July 2019
                Publication date (Print): 16 July 2019
                Volume: 51
                Issue: 1
                Pages: 77-89.e6
                Affiliations
                [1 ]The Francis Crick Institute, 1 Midland Road London NW1 1AT, UK
                [2 ]Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, SE1 9RT, UK
                [3 ]Present Address: Centre de Recherche scientifique et technique en Analyses Physico-Chimiques (C.R.A.P.C), Alger, Algérie
                Author notes
                [∗ ]Corresponding author brigitta.stockinger@ 123456crick.ac.uk
                [4]

                Lead Contact

                Article
                Publisher ID: S1074-7613(19)30224-9
                DOI: 10.1016/j.immuni.2019.05.004
                PMC ID: 6642154
                PubMed ID: 31229354
                SO-VID: 0afee749-e8ab-442b-b043-ffec847077ac
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 2 October 2018
                Date revision received : 28 February 2019
                Date accepted : 14 May 2019
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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