Smart, Michelle

Abstract MS is an inflammatory demyelinating disease of CNS with a presumed autoimmune origin. Prevalent data from animal model of disease, experimental autoimmune encephalomyelitis (EAE) suggests that myelin-specific CD4 T-cells play a major role in disease. Role of CD8 T-cells in MS/EAE has been enigmatic as it has been assigned either regulatory or pathogenic role in disease. Previously we have shown that PLPp91-110 peptide can induce inflammatory neurological disease in HLA-DR3 transgenic (Tg) mice. In order to understand the role of CD8 T cells in this humanized model, we generated HLA-DR3 Tg mice lacking CD8 T cells (DR3.CD8-/-). These mice showed earlier onset and more severe disease when compared to CD8 sufficient HLA-DR3 Tg mice indicating that CD8 T-cells plays a regulatory role. However, pathological analysis of DR3.CD8-/- mice with EAE showed less inflammation and demyelination in CNS compared to DR3.CD8 sufficient mice suggesting a second pathogenic role of CD8 T cells. Thus, our data suggests both a regulatory as well as a pathogenic role of CD8 T cells in EAE and possibly in MS. We have characterized both subsets in detail and show that CD8+CD122- T cells are regulatory subset of CD8 T cells and suppress CD4 T cells by inhibiting antigen presentation pathway, while CD8+CD122- T cells are pathogenic subset. Thus ours is the first study to show a dual role of CD8 T cells in the onset, incidence, progression, severity and pathogenesis of EAE/MS.