Unique invariant CD8+ T cell population persists in MS

Although historically overshadowed by CD4 T cells, and more recently by B cells, a number of lines of evidence point toward a potentially vital role of CD8 T cells in multiple sclerosis (MS) pathogenesis. CD8 T cells outnumber CD4 in the parenchyma of MS lesions and are abundant at the leading edge in chronic active lesions. Some studies have detected increased frequencies of myelin-specific CD8 T cells in patients with MS. Human leukocyte antigen (HLA)-A3 (A*0301), which encodes one of the major histocompatibility complex (MHC) class I proteins used for antigen recognition by CD8 T cells, doubles the risk of MS even in the absence of HLA-DR2 (DRB*1501, DQB*0602) genes that encode MHC II proteins used for antigen presentation to CD4 T cells. Furthermore, it has been demonstrated that myelin-specific CD8 T cells can induce an MS-like disease in HLA-A3 transgenic and wild-type mice. If antigen-specific CD8 T cells participate in MS pathogenesis, one might ask whether certain ones expand selectively and whether they persist. In this issue of Neurology® Neuroimmunology & Neuroinflammation, Held et al. examined CD8 T cells in 1 patient with MS over 18 years. A brain biopsy shortly after presentation demonstrated inflammatory demyelination. Using high-throughput Next Generation Sequencing, these investigators examined the CD8 T cell repertoire in this MS lesion and compared it to that found in the peripheral blood at subsequent time points. Each T cell recognizes a unique antigen and its specificity is primarily shaped by the combination of T cell receptor (TCR) a and b chain complementarity determining region (CDR) 3 regions, which are each formed by genetic recombination that links individual Va-Ja segments and separately connects Vb-Db-Jb sequences. Because the naive T cell repertoire is highly diverse, identification of a narrow array of T cell receptors in a particular location suggests clonal expansion of a small subset of antigen-specific T cells. Oligoclonal CD8 T cell populations in the blood, CSF, and brain of patients with MS were previously observed by TCR Vb sequencing. Held et al. took their clonal analysis a step further by combining the use of laser microdissection and single-cell PCR sequencing to analyze both the TCR a and b chains within individual CD8 T cells. They observed that a particular CD8 T cell clonotype bearing the Vb1-Jb2.3 TCRb chain was expanded in active brain lesions and that this dominance persisted. Surprisingly, their analysis revealed that the subset of CD8 Vb1 T cell clones contained a chains bearing the same CDR3a sequence, Va7.2-Ja33, that is unique to mucosal-associated invariant T (MAIT) cells, an innate-like CD8 T cell subset that accounts for up to 4% of peripheral T cells in humans. MAIT cells are identified by coexpression of CD161, which has been associated with secretion of proinflammatory cytokines, including interleukin-17. They are restricted by a unique nonpolymorphic MHC I–like molecule, MR1. Unlike classic MHC I–restricted CD8TCRa/b T cells, which recognize peptide antigens, MAIT cells recognize bacterial-derived metabolites, in particular derivatives of riboflavin, and are dependent on gut microbiota for their development. Even though MAIT cells made up only 1% of all CD8 T cells in MS brain lesions examined, persistent MAIT cell–related clonal populations were found in the blood 18 years after clinical onset. This is in contrast to other CD8 T cells, which lost their preferential clonal expansion and became polyclonal, similar to CD4 T cells. MAIT cells also exhibited a memory phenotype, indicating that they had been previously exposed to antigen. These results highlight the complexity of the CD8 T cell repertoire in MS. This report by Held et al. represents an important step forward in the analysis of the T cell repertoire found in MS. The degree of subclonal expansion of Va7.2/Vb1 CD8 T cells strongly suggests a local antigen-driven process, possibly within inflammatory