Specialization and targeting of CD4+ tissue resident memory T cells in EAE

Project Summary Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, axonal loss, and progressive disability. Similarly, its animal model, experimental autoimmune encephalomyelitis (EAE) is marked by CNS inflammation and demyelination. Circulating CD4+ T helper (Th) subsets have long been implicated in the pathogenesis of MS and EAE. Recently, T cells with tissue residence capacities and characteristics have been identified in CNS and the cerebrospinal fluid (CSF) there is a paucity of information regarding the specialization and functions of these of MS patients but cells during CNS autoimmunity. The study of CD4+ tissue resident memory (TRM) T cells in the context of EAE has been in part hampered by the lack of appropriate models and tools to track and eliminate these cells independently of other circulating memory and effector T cells. We have developed novel tools and models to further characterize and modulate CD4+ TRM during EAE. We hypothesize that CNS CD4+ TRMs form a reservoir of autoreactive T cells in the CNS which sustains disease and is poorly targeted by disease modifying therapies directed against circulating T cells. In this proposal, we will use these novel tools to specifically: 1) establish the diversity and specialization of CD4+ TRMs during EAE, 2) determine the mechanisms promoting the maintenance of CD4+ TRMs in the CNS, and 3) determine how to disrupt the tissue resident program in TRM and neutralize or eliminate them in the CNS. The completion of this proposal will help us understand how tissue resident memory T cells promote sustained autoimmunity and may lead to the development of novel therapies for MS and associated autoimmune diseases of the CNS.