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 an 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 (APC) 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 about regulatory CD8+ T cells both in MS and EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.

Multiple Sclerosis and T Lymphocytes: An Entangled Story

“…These APCs can efficiently activate CNS-reactive CD4 and CD8 T lymphocytes. Different regulatory T lymphocyte subsets have been shown to reduce the development and severity of EAE (Kleinewietfeld and Hafler 2014;Sinha et al 2014). Several groups reported that regulatory T cell subsets from MS patients have impaired regulatory functions compared to healthy donors (Kleinewietfeld and Hafler 2014;Sinha et al 2014).…”

Multiparameter Flow Cytometric Assays to Quantify Effector and Regulatory T-Cell Function in Multiple Sclerosis

“…Our understanding about the T cell-mediated immune processes that underlie MS pathogenesis and regulation has improved considerably over the past several years [14-17] However; the laboratory tests available for MS do not utilize this advanced level of knowledge. Diagnosis of MS still depends on a combination of radiographic, clinical and laboratory criteria.…”

Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis

“…Various types of Treg subtypes are now well recognized including thymic derived-nTregs, peripherally induced-iTregs, including Tr1 regulatory cells [21, 22], Th3 cells [23, 24] and CD8 + Tregs [19, 20, 25, 26]. Impaired immunosuppression by iTregs, including Tr1 cells or induced CD8 + Tregs has been associated with MS [27, 28].…”