PROJECT SUMMARY Developing new treatments to block multiple sclerosis (MS) while keeping beneficial immune function intact constitutes a major goal in the field. T cells are central drivers of MS pathogenesis. Our work shows that the transcriptional co-regulator OCA-B (gene symbol Pou2af1) is induced in stimulated primary CD4+ T cells, where it docks with its cognate transcription factor Oct1 to regulate immunomodulatory target genes including Il2, Il17a, Ifng, and Csf2 (Gmcsf). Interestingly, OCA-B drives the elevated expression of these genes only under a very narrow range of conditions. Primary stimulation of OCA-B deficient T cells results in few gene expression changes, however re-stimulating these cells after resting in culture results in gene expression changes of 500-fold or more. These results indicate that OCA-B controls gene expression specifically under conditions of antigen reencounter. We identified the molecular mechanism, which involves the removal of inhibitory chromatin modifications that otherwise accumulate to stably silence gene expression. Repeated antigen exposures are a necessary feature of autoimmunity. In vivo, OCA-B loss leaves T cell development and primary pathogen responses intact, but impairs the establishment of CD4+ T cell memory. In both mice and humans, T cells with memory-like phenotypes can underlie autoimmunity including MS. Human GWAS studies identify polymorphisms at the Ocab/Pou2af1 locus, as well as in binding sites for OCA-B and Oct1, as MS drivers. These findings suggest a potential “therapeutic window” in which targeting this pathway can be used to treat MS while preserving T cell development and primary immune responses. Consistently, we have shown that T cell-specific deletion of Oct1 blocks clinical and molecular manifestations of experimental autoimmune encephalomyelitis (EAE) while keeping immune responses to neurotropic viruses intact. OCA-B’s lymphoid-restricted expression pattern, and the viability and fertility of OCA-B germline null mice, make it a more promising potential drug target compared to Oct1. Our preliminary data indicate that T cell-specific OCA- B deletion also protects mice from classical EAE, and protects autoimmune-prone non-obese diabetic (NOD) mice from a relapsing EAE model, specifically at the relapse phase. Our overarching hypothesis is that OCA-B regulates key genes in autoreactive, pro-inflammatory Th1/Th17 CD4+ T cells to drive MS pathogenesis. We will realize the objectives of the study via two specific aims focused on OCA-B necessity and sufficiency: Aim 1: Determine the cellular and molecular basis of OCA-B promotion of EAE pathogenesis. Aim 2: Test OCA-B’s sufficiency in EAE pathogenesis.