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      Transcriptional Regulators of T Helper 17 Cell Differentiation in Health and Autoimmune Diseases

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          Abstract

          T helper (Th) 17 cells are a subtype of CD4 T lymphocytes characterized by the expression of retinoic acid-receptor (RAR)-related orphan receptor (ROR)γt transcription factor, encoded by gene Rorc. These cells are implicated in the pathology of autoimmune inflammatory disorders as well as in the clearance of extracellular infections. The main function of Th17 cells is the production of cytokine called interleukin (IL)-17A. This review highlights recent advances in mechanisms regulating transcription of IL-17A. In particular, we described the lineage defining transcription factor RORγt and other factors that regulate transcription of Il17a or Rorc by interacting with RORγt or by binding their specific DNA regions, which may positively or negatively influence their expression. Moreover, we reported the eventual involvement of those factors in Th17-related diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease, characterized by an exaggerated Th17 response. Finally, we discussed the potential new therapeutic approaches for Th17-related diseases targeting these transcription factors. The wide knowledge of transcriptional regulators of Th17 cells is crucial for the better understanding of the pathogenic role of these cells and for development of therapeutic strategies aimed at fighting Th17-related diseases.

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          Most cited references70

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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            Development, cytokine profile and function of human interleukin 17-producing helper T cells.

            T(H)-17 cells are a distinct lineage of proinflammatory T helper cells that are essential for autoimmune disease. In mice, commitment to the T(H)-17 lineage is dependent on transforming growth factor-beta and interleukin 6 (IL-6). Here we demonstrate that IL-23 and IL-1beta induced the development of human T(H)-17 cells expressing IL-17A, IL-17F, IL-22, IL-26, interferon-gamma, the chemokine CCL20 and transcription factor RORgammat. In situ, T(H)-17 cells were identified by expression of the IL-23 receptor and the memory T cell marker CD45RO. Psoriatic skin lesions contained IL-23-producing dendritic cells and were enriched in the cytokines produced by human T(H)-17 cells that promote the production of antimicrobial peptides in human keratinocytes. Our data collectively indicate that human and mouse T(H)-17 cells require distinct factors during differentiation and that human T(H)-17 cells may regulate innate immunity in epithelial cells.
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              Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

              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
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 March 2020
                2020
                : 11
                : 348
                Affiliations
                [1] 1Neuroimmunology Unit, IRCSS Fondazione Santa Lucia , Rome, Italy
                [2] 2Department of Biology and Biotechnology Charles Darwin, Sapienza University , Rome, Italy
                Author notes

                Edited by: Nicola Ivan Lorè, IRCCS San Raffaele Scientific Institute, Italy

                Reviewed by: Rami Bechara, University of Pittsburgh, United States; Samuele Notarbartolo, Istituto Nazionale Genetica Molecolare (INGM), Italy; Laura A. Solt, The Scripps Research Institute, United States

                *Correspondence: Elisabetta Volpe e.volpe@ 123456hsantalucia.it

                This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.00348
                7080699
                6965682a-4b4d-433e-a947-94638ba2ede7
                Copyright © 2020 Capone and Volpe.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 December 2019
                : 13 February 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 103, Pages: 8, Words: 6870
                Funding
                Funded by: Ministero della Salute 10.13039/501100003196
                Award ID: GR-2016-02361163
                Funded by: Fondazione Italiana Sclerosi Multipla 10.13039/100007366
                Award ID: FISM2016/R/31
                Categories
                Immunology
                Mini Review

                Immunology
                t helper 17 cells,interleukin-17,retinoic acid receptor related orphan nuclear receptor γt,multiple sclerosis,crohn's disease,rheumatoid arthritis,psoriasis

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