Inhibiting CNS resident memory T cells driving neuroinflammation

About This Grant

Project Summary Multiple sclerosis (MS) is a chronic, autoimmune-mediated disease of the central nervous system characterized by demyelination, axonal loss, and progressive disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model which shares specific particularities with MS, has helped develop current disease modifying therapies (DMTs) used to treat MS patients and has been instrumental to understand mechanisms behind disease development and progression. While current disease modifying therapies have been beneficial to improve the health of MS patients, a significant proportion of them continue to experience relapses, and disease tend to worsen over time suggesting the inflammatory and autoimmune response could be sustained in the CNS. Memory CD4+T cells and B cells have been implicated in the pathogenesis of MS. While most memory T cells can be sampled in the blood because they circulate between lymphoid tissues, blood and non-lymphoid tissues; and their egress from lymphoid tissues and migration to the CNS can be stopped by DMTs, a small fraction of memory T cells called tissue resident memory T cells (TRM) have unique proprieties and resides in non- lymphoid tissues. T cells with TRM phenotype have been identified in the CSF and CNS of individual with from MS. 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. Using a newly developed TRM dependent model of EAE and a targeted CRISPR screen, we will: 1) Identify molecular cues that inhibit TRM maintenance in the CNS during EAE, 2) Validate individually the effect of selected genes on TRM maintenance and EAE progression. Our approach is poised to identify novel inhibitory genes for TRM and therefore could provide the basis for the development of new MS therapies which could work independently or in conjunction with current DMTs. In addition, our findings will provide novel fundamental information regarding TRM and means to inhibit them.