Treatment of autoimmune demyelination by autoregulatory CD8+ T-cells (115.24)

Abstract

Abstract Immune dysregulation is believed to be the causative factor in the debilitating neurological disease Multiple Sclerosis (MS). We have recently shown that neuroantigen-specific auto-reactive regulatory (autoregulatory) CD8+ T-cells are capable of suppressing the murine model of MS, experimental autoimmune encephalomyelitis (EAE), a disease mediated by neuroantigen-specific CD4+ T-cells. We now show that deficiency of CD8+ T-cells correlates with more severe disease and an increase in IL-17+ and TCRVβ8.2+ CD4+ T-cell responses with reduction in IL-10+ CD4+ T-cells. Disease suppression by autoregulatory CD8+ T-cells is dependent on recognition of cognate antigen in vivo in the context of MHC Class I and requires IFN-γ and perforin production by CD8+ T-cells, suggesting a cytotoxic/suppressor mechanism. Suppression mediated by direct CD8-CD4 interactions is suggested by the ability of these cells to inhibit adoptively transferred disease and direct in vitro killing of neuroantigen-loaded CD4+ T cells. Finally, neuroantigen-specific CD8+ T-cells were able to traffic to the central nervous system (CNS) during ongoing inflammation, suggesting both a peripheral and central mechanism of action. These studies define a novel and unexpected immune regulatory function for tissue-reactive “autoregulatory” CD8+ T-cells that can be harnessed for the development of immunotherapeutic intervention in MS and other autoimmune diseases.