Involvement of CD8(+) T Cells in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by focal demyelination patches associated with inflammatory infiltrates containing T lymphocytes. For decades, CD4(+) T cells have been recognized as playing a major role in the disease, especially in animal models, which has led to the development of several therapies. However, interest has recently developed in the involvement of CD8(+) T cells in MS following the analysis of infiltrating T cells in human brain lesions. A broad range of evidence now suggests that the pathological role of this T cell subset in MS may have been underestimated. In this review, we summarize the literature implicating CD8(+) T cells in the pathophysiology of MS. We present data from studies in the fields of genetics, anatomopathology and immunology, mainly in humans but also in animal models of MS. Altogether, this strongly suggests that CD8(+) T cells may be major effectors in the disease process, and that the development of treatments specifically targeting this subset would be germane.

Keywords: CD8+ T cells; autoimmunity; multiple sclerosis.

Figure 1

Infiltrating T cells are mainly CD8⁺ T cells and express GZM-B. Example of staining with DAPI (blue), CD3 (red), CD8 (gray), and GZM-B (green). The line in the pictures indicates 20 μm. Stars show CD3⁺CD8⁺GZM-B⁺ and arrows show CD3⁺CD8⁻GZM-B⁻ cells. GZM-B: granzyme-B. From personal data.

Figure 2

Steps to elucidate to better understand CD8⁺ autoreactivity mechanisms in MS disease. A peripheral inflammation induced by pathogens (such as EBV) could occur in case of uncontrolled infection. This can lead to the activation or reactivation of CD8⁺ T cells, and the expression of several molecules implicated in adhesion, migration, and cytotoxicity, currently not well characterized. In this inflamed state, the BBB could overexpress adhesion and chimoattractant molecules, leading to the entry of CD8⁺ T cells into the CNS. In situ, CD8⁺ T cells could be reactivated by resident APC presenting target Ag(s), unknown for now. This could lead to the clonal expansion of CD8⁺ T cells along with the secretion of proinflammatory molecules. Finally, in this step, CD8⁺ T cells could be able to mediate damage to resident cells and axons potentially by the recognition of CNS derived peptides. Ag: antigen; GZM-B: granzyme-B; BBB: blood–brain barrier; CNS: central nervous system; MS: multiple sclerosis; EBV: Epstein–Barr virus; APC: antigen-presenting cell; TCR: T-cell receptor; MCAM: melanoma cell adhesion molecule; VCAM-1: vascular cell adhesion molecule 1; DC: dendritic cell; MHC-I: major histocompatibility complex I; CCR2: C–C chemokine receptor type 2; CCL2: C–C chemokine ligand 2; IFNγ: interferon γ; IL-17: interleukin-17.