Elucidating the Mechanisms of Autoregulatory CNS-Specific CD8+ T Cell-Mediated Amelioration of Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that afflicts approximately 500,000 individuals within the US. Experimental autoimmune encephalomyelitis (EAE) is the conventional animal model used to study MS, induced by immunization of mice with myelin-related antigens. The etiology of MS remains unknown, and disease is thought to be initiated by the formation of acute inflammatory lesions and an increase in blood-brain barrier permeability. CD4+ T cells, CD8+ T cells, B cells, as well as other immune cells are detected in the inflammatory CNS lesions of MS patients. CD8+ T cells predominate in MS lesions; however, their role remains controversial. Previous research from our lab demonstrated a novel and unexpected regulatory role for CNS-specific CD8+ T cells in both MS and EAE. In the models thus far, CNS-specific CD8+ T cell responses are induced by active immunization with exogenous antigens. One of my projects aims to evaluate whether distinct functionality may be induced in CD8+ responses toward endogenously processed and presented epitopes. This involves the generation of recombinant Listeria monocytogenes strains that express peptides demonstrated to elicit CD8+ T cell responses in EAE. Using the murine model of listeriosis, we propose to investigate whether these CD8+ T cell responses are encephalitogenic or regulatory in nature, and to understand the cellular and molecular interactions that determine this functional differentiation.

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