Neuroantigen-specific CD8+ regulatory T-cell function is deficient during acute exacerbation of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS-specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25− T-cells when stimulated by their cognate antigen. While CD8+ T-cell-mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naïve MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology.

Introduction

Multiple sclerosis (MS) is the most common disabling neurological disease of young people, typically presenting as a relapsing–remitting form (RRMS). MS is thought to be immune-mediated and is characterized by temporally and spatially separated central nervous system (CNS) lesions that may be accompanied by acute exacerbation of clinical symptoms, which remit over time with limited accumulating disability. The immune dysregulation that underlies the pathology of MS and its clinical exacerbations remain poorly understood. Much of our understanding of the immunology of MS derives from work in the murine model, experimental autoimmune encephalomyelitis (EAE). The vast majority of studies in MS and EAE have focused on the role of CD4+ T-cells as mediators and regulators of disease. The preponderant belief is that MS and EAE are mediated through CNS-specific CD4+ Th1/Th17 responses and regulated by CD4+ regulatory T-cells [1]. However, considerable evidence points to an important role for CD8+ T-cells in the pathogenesis and/or regulation of MS and EAE [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. CNS lesions show a predominance of CD8+ T-cells with oligoclonal expansion [4], indicating an active role at the site of pathology. While it is thought that these cells represent a key pathogenic element of MS lesions, neither the antigenic specificity of these cells nor their role has been elucidated. MS patients show a high prevalence of CNS-specific CD8+ T-cell responses in their circulation [3]. These cells appear to have a mixed functional phenotype in that they express cytotoxic/inflammatory as well as regulatory effector molecules [3]. Again, the intuitive function attributed to these responses is that of pathogenesis. However, their role has not been adequately investigated. Moreover, healthy subjects also harbor such responses, raising the possibility that they may not be purely pathogenic.

Antigen-specific immune regulation has high therapeutic potential. Global defects in immune regulatory T-cell (T_reg) function have been demonstrated in a wide variety of human immune-mediated diseases [14], [19], [20], [21], [22], [23], [24], [25], [26], [27]. In most cases, antigenic specificity of the regulatory population is poorly defined and this would be key in the ability to expand and utilize such populations. In the current study, we investigated the role of neuroantigen-specific CD8+ T-cells in MS and discovered an unexpected, novel and clinically relevant immune regulatory role for autoantigen-specific T-cells. This role has both biologic and therapeutic implications.