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Abstract

OBJECTIVES: To characterize phenotypes of T cells that accumulated in multiple sclerosis (MS) lesions, to compare the lesional T-cell receptor (TCR) repertoire of T-cell subsets to peripheral blood, and to identify paired alpha and beta chains from single CD8(+) T cells from an index patient who we followed for 18 years.; METHODS: We combined immunohistochemistry, laser microdissection, and single-cell multiplex PCR to characterize T-cell subtypes and identify paired TCRalpha and TCRbeta chains from individual brain-infiltrating T cells in frozen brain sections. The lesional and peripheral TCR repertoires were analyzed by pyrosequencing.; RESULTS: We found that a TCR Vbeta1(+) T-cell population that was strikingly expanded in active brain lesions at clinical onset comprises several subclones expressing distinct yet closely related Valpha7.2(+) alpha chains, including a canonical Valpha7.2-Jalpha33 chain of mucosal-associated invariant T (MAIT) cells. Three other alpha chains bear striking similarities in their antigen-recognizing, hypervariable complementarity determining region 3. Longitudinal repertoire studies revealed that the TCR chains that were massively expanded in brain at onset persisted for several years in blood or CSF but subsequently disappeared except for the canonical Valpha7.2(+) MAIT cell and a few other TCR sequences that were still detectable in blood after 18 years.; CONCLUSIONS: Our observation that a massively expanded TCR Vbeta1-Jbeta2.3 chain paired with distinct yet closely related canonical or atypical MAIT cell-related alpha chains strongly points to an antigen-driven process in early active MS brain lesions.