Myelin-specific CD8+ T cells exacerbate CNS autoimmunity

Abstract

Abstract Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Although the pathogenic pathways of MS are not fully understood, myelin-specific T cells are hypothesized to initiate disease. Myelin-specific CD4+ T cells have been the main focus of MS research and animal models of MS have relied exclusively on the activity of CD4+ T cells. However, a substantial body of data from MS patients indicate that CD8+ T cells are also involved in MS pathogenesis. We hypothesized that recruitment of myelin-specific CD8+ T cells to the site of inflammation initiated by CD4+ T cells could influence disease. To test our hypothesis, we use a mouse model of MS, experimental autoimmune encephalomyelitis (EAE) in which adoptive transfer of CD4+ T cells specific for myelin oligodendrocyte glycoprotein (MOG) induces CNS autoimmunity. To determine the influence of CD8+ T cells, we introduce CD8+ T cells from a TCR-transgenic mouse model expressing a TCR specific for a MHC class I-restricted epitope of myelin basic protein (MBP) into the periphery of mice just after disease induction. We found that the recruitment of the MBP-specific but not control CD8+ T cells exacerbated CD4+ T cell-initiated EAE. Furthermore, recruitment of MBP-specific CD8+ T cells increases the number of MOG-specific CD4+ T cells within the CNS at peak disease. Interestingly, mice that received MBP-specific CD8+ T cells exhibited an increase in symptoms associated with brain inflammation. These data suggest that the interplay between CD4+ and CD8+ T cells specific for two different myelin proteins is critical for determining the manifestation of CNS autoimmune disease.