Molecular mechanisms of Th17 plasticity in MS

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DESCRIPTION (provided by applicant): Multiple sclerosis (MS) and its mouse model (experimental autoimmune encephalomyelitis; EAE) are autoimmune diseases of the central nervous system initiated and propagated by auto-reactive CD4+ T cells. Two subsets of CD4+ T cells, Th1 and Th17 cells have been implicated in the pathogenicity of autoimmune diseases and in particular MS. However, the relative contribution of myelin specific Th1 and Th17 cells in the development of central nervous system (CNS) autoimmunity remains controversial since neither IL-17F, IL- 17A, nor IFN-γ deficient mice are fully protected from the development of CNS autoimmunity. In contrast, IL- 23p19- and IL-23 receptor (IL-23R) deficient mice are highly resistant to the development of EAE. Furthermore, in inflamed tissues of patients with autoimmune diseases, Th cells co-expressing IFN-γ and IL-17 have been identified in significant number. Their increase frequency in target tissues during autoimmunity suggests an important role of these cells in the disease process. However, the genesis, stability and function of these cells in autoimmunity remain enigmatic. We have determined that most CNS-infiltrating T cells during the course of EAE express the IL-23R irrespective of their cytokine production (IL-17 and/or IFN-γ) because they originate from Th17 cells. We further show that IL-23 plays a critical role in Th17 plasticity as it promotes the emergence of IL-17+ IFN-γ+ T cells (Th17/g) from Th17 cells. Although Th17/g cells expressed T-bet, IFN-γ production in these cells was not controlled by T-bet or other IFN-γ-promoting transcription factors. In contrast, we identified AhR as a key transcription factor driving the production of IFN-γ by Th17 cells in response to IL-23. We have also confirmed the importance of IL-23 for the generation of these cells in human CD4+ T cells. In addition, we have initiated a genome-wide analysis of DNase hypersensitivity sites in human Th1 and Th17 cells subsets using Solexa sequencing. Our results show that we can identify transcription factors binding sites and distinguish epigenetic marks in individual T cell subsets using this technique. In this proposal, we will test our overarching hypothesis that TH17/g cells are pathogenic cells in CNS-specific autoimmunity, are driven by IL-23 through an AhR-dependent mechanism and present with selective genetic alterations in MS patients. Together the completion of this study will not only delineate the function of Th17/g cells in autoimmunity but also determine the mechanisms by which these cells are generated and can be regulated in mice and humans.