Therapeutic intervention in relapsing autoimmune demyelinating disease through induction of myelin-specific regulatory CD8 T cell responses

Abstract

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). We have shown that CNS-specific CD8 T cells (CNS-CD8) possess a disease suppressive function in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous studies have focused on the role of these cells predominantly in chronic models of disease, but the majority of MS patients present with a relapsing-remitting disease course. In this study, we evaluated the therapeutic role of CD8 T cells in the context of relapsing-remitting disease (RR-EAE), using SJL mice. We found that PLP178-191- and MBP84-104-CD8 ameliorated disease severity in an antigen-specific manner. In contrast, PLP139-151-CD8 did not suppress disease. PLP178-191-CD8 were able to reduce the number of relapses even when transferred during ongoing disease. We further ascertained that the suppressive subset of CD8 T cells was contained within the CD25 + CD8 T cell compartment post-in vitro activation with PLP178-191. Using Listeria monocytogenes (LM) encoding CNS antigens to preferentially prime suppressive CD8 T cells in vivo, we show that LM infection induced disease suppressive CD8 T cells that protected and treated PLP178-191 disease. Importantly, a combination of PLP178-191-CD8 transfer boosted by LM-PLP175-194 infection effectively treated ongoing disease induced by a non-cognate peptide (PLP139-151), indicating that this approach could be effective even in the context of epitope spreading. These data support a potential immunotherapeutic strategy using CD8 transfer and/or LM vaccination to boost disease regulatory CD8 T cells. Keywords: EAE, CD8 T cells, Regulatory T cells, Therapy