Dissecting the role of the ATF4 stress response in T cell-mediated inflammation

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 DESCRIPTION (provided by applicant) Reactive oxygen species (ROS) play a major role in the pathogenesis of chronic inflammatory and autoimmune diseases. It is well established that ROS modulate T cell-mediated immune responses. However, little is known about underlying molecular mechanisms of how ROS regulate T cell immune responses and how T cells adapt to high levels of ROS. Our goal is to elucidate the transcriptional network regulating T cell adaption to oxidative stress. In preliminary studies, we found ROS were elevated to much greater levels in CD4+ T cells cultured in Th1 conditions when compared to those cultured in Th0 and Th17 conditions. In further gene profiling studies, we demonstrated that ROS induced the gene expression signature of activating transcription factor-4 (ATF4) in activated Th1 cells in vitro an MOG-specific T cell in vivo. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates cellular redox state and amino acid metabolism. We demonstrated that experimental allergic encephalomyelitis (EAE) was exacerbated in ATF4 deficient mice compared with wild type (WT) mice. Consistent with clinical scores of EAE, the number of autoreactive Th1 cells was decreased whereas that of autoreactive Th17 cells was elevated in ATF4 deficient mice compared with WT mice. We further showed that in vitro ATF4 deficiency in T cells resulted in great reduction of IFN-γ production in Th1 cultures and modest reduction of IL-17 in Th17 cultures. In contrast, in vitro, ATF4 deficiency in antigen presenting cells (APC) resulted in no change in IFN-γ production in Th1 cultures but an increase in IL-17 in Th17 cultures. Based on these new findings, we hypothesize that ATF4 promotes Th1 and suppresses Th17 immune responses in pathological conditions involving the oxidative stress. To test this hypothesis, we propose the following specific aims: Specific Aim 1. Determine the T cell autonomous role of ATF4 in Th1/Th17 differentiation in vivo. Specific Aim 2. Determine the role of ATF4 within myeloid cells in T helper cell differentiation in vivo.