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      A role for BATF3 in T H9 differentiation and T cell driven mucosal pathologies

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          Abstract

          T helper 9 (T H9) cells are important for the development of inflammatory and allergic diseases. The T H9 transcriptional network converge signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as strong inducer of mouse and human T H9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under T H9 and T H9-TL1A polarizing conditions. In vivo, using a T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, T H9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3 −/− T H9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes T H9 cell differentiation and function and define a role of BATF3 in T cell driven mucosal inflammation.

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          Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.

          Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8alpha+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8alpha+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8alpha+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
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            A validated regulatory network for Th17 cell specification.

            Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. Copyright © 2012 Elsevier Inc. All rights reserved.
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              STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.

              Interleukin-17 (IL-17)-producing helper T (TH) cells, named as TH(IL-17), TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor gamma-T (RORgamma t), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORgamma t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.
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                Author and article information

                Journal
                101299742
                35518
                Mucosal Immunol
                Mucosal Immunol
                Mucosal immunology
                1933-0219
                1935-3456
                6 December 2018
                07 January 2019
                May 2019
                07 July 2019
                : 12
                : 3
                : 644-655
                Affiliations
                [1 ]F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Los Angeles, CA 90048, USA
                [2 ]Regenerative Medicine Institute, Los Angeles, CA 90048, USA
                [3 ]Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
                [4 ]Current address: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino Fujisawa-shi Kanagawa, 252-0880 Japan
                Author notes

                Author Contributions

                M.T., H.H., L.T., M.W., B.S., M.W., J.N., J.S., A.N.-W., R.B., Y.W., J.T., V.F., and K.M. performed experiments, analyzed data, and critically reviewed the manuscript. A.P., J.T., and Y.W. performed RNA-Seq data analysis. M.T., S.T., and K.M. designed the experiments. M.T. and K.M. wrote the manuscript.

                [* ]To whom correspondence should be addressed: Kathrin S. Michelsen, Ph.D. F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Davis Research Building, RM 4066, 110 George Burns Road, Los Angeles, CA 90048, USA, Phone: (310) 423-0539 FAX: (310) 423-0224, kathrin.michelsen@ 123456cshs.org
                Article
                NIHMS1515485
                10.1038/s41385-018-0122-4
                6462229
                30617301

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                Immunology

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