CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis

Abstract

The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4(+) T-cells as mediators and regulators of disease. Interestingly, CD8(+) T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial. Several animal models and MS patient studies support a pathogenic role for CNS-specific CD8(+) T-cells, whereas we and others have demonstrated a regulatory role for these cells in disease. In this review, we describe studies that have investigated the role of CD8(+) T-cells in MS and EAE, presenting evidence for both pathogenic and regulatory functions. In our studies, we have shown that cytotoxic/suppressor CD8(+) T-cells are CNS antigen-specific, MHC class I-restricted, IFNγ- and perforin-dependent, and are able to inhibit disease. The clinical relevance for CD8(+) T-cell suppressive function is best described by a lack of their function during MS relapse, and importantly, restoration of their suppressive function during quiescence. Furthermore, CD8(+) T-cells with immunosuppressive functions can be therapeutically induced in MS patients by glatiramer acetate (GA) treatment. Unlike CNS-specific CD8(+) T-cells, these immunosuppressive GA-induced CD8(+) T-cells appear to be HLA-E restricted. These studies have provided greater fundamental insight into the role of autoreactive as well as therapeutically induced CD8(+) T-cells in disease amelioration. The clinical implications for these findings are immense and we propose that this natural process can be harnessed toward the development of an effective immunotherapeutic strategy.

Keywords: CD8; EAE; T-cells; immune regulation; multiple sclerosis.

Figure 1

Role of CD8⁺ T-cells in MS/EAE. While the antigenic specificity of pathogenic CD8⁺ T-cells remains unknown, their pathogenic function is mainly attributed to pro-inflammatory cytokine secretion (in the peripheral immune system and potentially in the CNS) as well as cytotoxicity toward oligodendrocytes in the CNS. On the other side, several lines of evidence indicate a regulatory role for CD8⁺ T-cells in both MS and EAE. Neuroantigen-specific autoregulatory T-cells are classically MHC Class I restricted, whereas there are also examples of HLA-E/Qa1-restricted regulatory T-cells that may be naturally occurring or induced through therapy. Mechanisms for CD8⁺ T-cell-mediated regulation include secretion of cytokines such as IL-10 and IFNγ, cytotoxicity toward pathogenic immune cells and modulation of APC functions, both in the periphery and possibly in the CNS.