Given that ROR γt is expressed in both pathogenic and non-pathogenic Th17 cells in vivo, it is unlikely that the full repertoire of ROR γt-dependent transcriptional activity in vivo has been captured by previous transcriptional profiling experiments using Th17 cells generated in vitro. 17 In mouse and human CD4 + T cells, as well as in γδ Τ cells, IL-1 β and IL-23 are important, both for high-level IL-17A production and development of autoimmune inflammation. 16 In addition to ROR γt and T-bet, the Runx family transcription factors, namely Runx1 and Runx 3, have been recently shown to control IFN- γ production by pathogenic Th17 cells. 13 – 15 ‘Pathogenic’ Th17 cells express Th17 cytokines together with IFN- γ they express both ROR γt and T-bet, and they are distinguished from non-pathogenic Th17 cells by their selective expression of the multidrug transporter, MDR1. Interleukin-23 is critical for both the maintenance of IL-17A expression as well as pathogenic Th17 cell function in experimental autoimmune encephalomyelitis (EAE). The differentiation of Th17 cells in vivo is more complicated, and can lead to functionally distinct pro-inflammatory and anti-inflammatory Th17 cell subsets. 7 – 9 Differentiation of Th17 cells requires the retinoic acid receptor-related orphan nuclear receptor ROR γt, 10, 11 which is induced during human and mouse naive T-cell activation in the presence of cytokines such as IL-6, transforming growth factor- β (TGF- β) and IL-1 β. 4 – 7 Human monoclonal antibodies against IL-17A or IL-17 receptor A (IL-17RA) have demonstrated clinical efficacy in both psoriasis and rheumatoid arthritis. In contrast, Th17 cells are defined by production of IL-17A, IL-17F, IL-21 and IL-22, and these cells play a central role in autoimmune pathogenesis. 1 – 4 Th1 cells are characterized by transcription factor T-bet and the production of interferon- γ (IFN- γ), whereas Th2 cells are characterized by transcription factor GATA3 and the production of interleukin-4 (IL-4), Induced Treg cells, like their thymic-derived ‘nTreg’ cell counterparts, selectively express the transcription factor Foxp3 and suppress bystander T-cell activation to regulate inflammatory T-cell responses. Naive CD4 + T cells differentiate into a variety of effector and regulatory subsets, including T helper type 1 (Th1), Th2, induced T regulatory (iTreg) cells, and Th17 cells. These results reveal novel disease-associated genes regulated by ROR γt during inflammation in vivo, and provide an early read on potential disease indications and safety concerns associated with pharmacological targeting of ROR γt. Interestingly, more than 30 genes are related with SMAD3, a transcription factor involved in the Th17 cell differentiation. Importantly, we show that TMP778 acts in vivo to repress the expression of more than 150 genes, most of which fall outside the canonical Th17 transcriptional signature and are linked to a variety of inflammatory pathologies in humans. We show that the ROR γt inverse agonist TMP778 acts potently and selectively to block mouse Th17 cell differentiation in vitro and to impair Th17 cell development in vivo upon immunization with the myelin antigen MOG 35–55 plus complete Freund's adjuvant. Whereas small molecule ROR γt antagonists impair Th17 cell development and attenuate autoimmune inflammation in vivo, the broader effects of these inhibitors on ROR γt-dependent gene expression in vivo has yet to be characterized. The orphan nuclear receptor, retinoic acid receptor-related orphan nuclear receptor γt (ROR γt), is required for the development and pathogenic function of interleukin-17A-secreting CD4 + T helper type 17 (Th17) cells.
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