Immune regulation of multiple sclerosis by CD8+ T cells

Abstract

The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with underlying T cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology. It is still unclear whether these cells represent pathogenic immune responses or disease-regulating elements. Through studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), we have discovered two novel CD8+ T cell populations that play an essential immunoregulatory role in disease: (1) MHC class Ia-restricted neuroantigen-specific "autoregulatory" CD8+ T cells and (2) glatiramer acetate (GA/Copaxone(®)) therapy-induced Qa-1/HLA-E-restricted GA-specific CD8+ T cells. These CD8+ Tregs suppress proliferation of pathogenic CD4+ CD25- T cells when stimulated by their cognate antigens. Similarly, CD8+ Tregs significantly suppress EAE when transferred either pre-disease induction or during peak disease. The mechanism of disease inhibition depends, at least in part, on an antigen-specific, contact-dependent process and works through modulation of CD4+ T cell responses as well as antigen-presenting cells through a combination of cytotoxicity and cytokine-mediated modulation. This review provides an overview of our understanding of CD8+ T cells in immune-mediated disease, focusing particularly on our findings regarding regulatory CD8+ T cells both in MS and in EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.

Figure 1. Model for neuroantigen-specific or GA-induced CD8+ T cell-mediated regulation of multiple sclerosis

MHC class Ia or HLA-E-restricted CD8+ T cells use a combination of IFN-γ mediated-immune modulation and perforin-mediated cytotoxic mechanisms to curb inflammatory responses associated with immune cells. These CD8-Tregs can be induced by IDO-expressing APC and further secretion of IFN-γ by CD8-Tregs can potentially act in a positive feedback loop to boost IDO production in APC. The ultimate effect of actions on APC and CD4+ Th1/Th17 cells is the inhibition of pathogenic T cell responses in the periphery and in the CNS, resulting in control of disease pathology.