ABSTRACT: The central nervous system (CNS) is home to three major classes of glia: astrocytes, microglia, and oligodendrocytes. Recently, a fourth class of glia has been recognized, called oligodendrocyte progenitor cells (OPCs). Like microglia, OPCs have a stellate morphology and are “tiled”, spanning defined territories across the gray and the white matter. For a long time, our vision of OPC function was limited to generation of mature oligodendrocytes. This dogma is challenged by recently published studies suggesting that OPCs could serve other role(s) in the CNS. Indeed, a nascent body of work is uncovering an intricate role for these cells in the context of inflammation. For example, OPCs have been shown to express cytokines and participate in the recruitment of peripheral monocytes. Following injury, OPCs can release IL-33, a key alarmin that orchestrates the immune response. Finally, in animal models of MS, OPCs have been shown to present antigen and respond to inflammatory cytokines, suggesting that they are active regulators of disease in MS. Taken together, these data demonstrate that OPCs are not simple bystanders, but could participate in the inflammatory response in the CNS. Our long-term goal is to shed light on the role of OPCs in the CNS, focusing on their alternate immune functions, in an effort to develop novel MS therapeutics. The foundation of this proposal is formed by the observations that low-density lipoprotein receptor-related protein-1 (LRP1) is expressed by OPCs and functions to facilitate phagocytosis of myelin and antigen cross- presentation. Our preliminary data show that deletion of LRP1 in OPCs promotes remyelination in animal models of MS. Our central hypothesis is that, during demyelination, OPCs cross-present antigens to CD8 T cells in an LRP1 dependent manner, leading to OPC cell death and impairing remyelination. Guided by strong evidence, this hypothesis will be addressed by pursuing three specific aims: 1: Assess the role of LRP1 in the OPC-mediated inflammatory response, 2: Assess pharmacological and genetic manipulation of OPC antigen cross-presentation in promoting myelin repair, 3: Determine the impact of OPC antigen cross-presentation on T cell functions. We will use in vivo animal models of demyelination (cuprizone and EAE) and in vitro cultures of OPCs and T cells to test our hypothesis. Our approach is innovative because it will utilize novel mouse strains and state of the start single-cell sequencing to generate new scientific knowledge of alternate functions of OPCs in the context of remyelination. The proposed research is significant because it will test whether antigen presentation via LRP1 represents a novel target for therapy development in MS and other demyelinating disorders. The insights gained from our studies will lead to fundamental advances in understanding how OPCs contribute to inflammation.