Spotlight on CD8 T cells in MS

IMMUNOBIOLOGY

Multiple sclerosis (MS) involves an autoimmune response directed against central nervous system (CNS) myelin antigens. The histologic features involving both lymphocyte and macrophage infiltration into the CNS, the role of interferon gamma (IFN-γ) in causing disease exacerbations, and an animal model mediated by CD4⁺ T-helper 1 (Th1) lymphocytes have led to the assumption that CD4⁺ T cells are the primary immune culprit leading the autoimmune attack against myelin in MS. The precise identification of the target myelin antigen(s) has been debated for decades. In this issue, Crawford and colleagues (page 4222) focus on the individual T-cell types mediating the antimyelin response and the potential myelin targets using a wide spectrum of epitopes.

Crawford et al identify CNS-specific CD4⁺ and CD8⁺ T cells in untreated MS patients using a novel and comprehensive approach. Proliferative responses are evaluated using 530 serial overlapping peptides spanning the entire sequence of 9 CNS autoantigens, including myelin basic protein (MBP), myelin proteolipid protein (PLP), myelin-associated oligodendrocytic basic protein (MOBP), and 6 others. Blood mononuclear cells from patients at various stages of disease (relapsing-remitting, primary progressive, secondary progressive) are assessed for proliferation by carboxyfluorescien diacetate succinimidyl ester (CFSE) staining, specificity, phenotype, and cytokine secretion. A high prevalence of myelin peptide–reactive CD4⁺ T cells is demonstrable in healthy subjects and all groups of MS patients, with no significant differences in specificity between groups. Myelin-reactive CD4⁺ T cells in MS are more differentiated than healthy subjects with significantly increased IFN-γ and decreased interleukin 4 (IL-4), IL-5, and CCR5. What is surprising about the results of Crawford et al is the extent of CD8⁺ T-cell responses, particularly in remitting-relapsing MS (RRMS). More than 50% of the RRMS group responded to the MOBP peptides, with CD8 responses in MS characterized by increased IFN-γ, IL-10, and CXCR3.

CD8 T cells are known to be present in the CNS infiltrates in MS, and Babbe et al¹  reported that these T cells expand within the lesion as evidenced by oligoclonality of the T-cell receptors. The question is, what is their function in the milieu of the CNS? Evidence for 2 opposing roles has emerged. First, in the experimental autoimmune encephalomyelitis (EAE) model of MS, MBP-specific CD8 T-cell clones transferred severe neurologic signs indicative of upper motor neuron impairment to naive or severe combined immunodeficiency (scid) mice.²  A role for IFN-γ was observed, arguing for a pathologic contribution of the transferred CD8⁺ cells. Second, evidence suggests a regulatory role for CD8⁺ T cells in EAE and MS. Mice genetically depleted of CD8 T cells show greater relapses, implicating the CD8 cell in maintaining a state of disease remission.³  Crawford et al showed that proliferating CD8 T cells in MS secrete both IFN-γ and IL-10, suggesting a mixture of both pathologic and regulatory populations. Interestingly, this group earlier showed that glatiramer acetate (GA) therapy administered to MS patients restored levels of GA-specific CD8⁺ T cells to control levels.⁴  Thus, increasing evidence points to both a pathologic and regulatory role for the CD8 T cells in MS, with future therapies perhaps targeted toward increasing the regulatory population.