How myelin-specific CD8 T cells contribute to CNS autoimmunity.

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). CD4 T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE). However, the extensive clinical and pathological heterogeneity seen in MS suggests that multiple pathways may be involved. Substantial evidence from patients with MS point to a role for CD8 T cells in disease pathogenesis. The ability of myelin-specific CD8 T cells to induce CNS autoimmunity and to exacerbate EAE initiated by CD4 T cells demonstrates a pathogenic role; however, the mechanisms by which CD8 T cells exert either activity have not been defined. Here we show that myelin basic protein (MBP)-specific CD8 T cells employ distinct mechanisms to induce CNS autoimmunity versus exacerbate EAE initiated by CD4 T cells. MBP-specific CD8 T cells activated by peripheral viral infection require both IFNγ and perforin to initiate EAE. In contrast, naïve MBP-specific CD8 T cells recruited to the CNS during CD4 T cell initiated-EAE exacerbate disease via a Fas ligand-dependent mechanism that is independent of IFNγ and perforin expression. Interestingly, MBP-specific CD8 T cells exacerbated brain but not spinal cord inflammation. Reactive oxygen species production by monocyte-derived cells was elevated in the brain but not spinal cord only if MBP-specific CD8 T cells expressed Fas ligand. These results demonstrate that the ability of myelin-specific CD8 T cells to exert distinct effector functions with diverse pathologic outcomes may contribute to the heterogeneity seen in MS.