A new clustering method identifies multiple sclerosis‐specific T‐cell receptors

Objective To characterize T-cell receptors (TCRs) and identify target epitopes in multiple sclerosis (MS). Methods Peripheral blood mononuclear cells were obtained from 39 MS patients 19 healthy controls (HCs). TCR repertoires for α/β/δ/γ chains, diversity, V/J usage determined by next-generation sequencing. β chain compared with affectation status using a novel clustering method, Grouping of Lymphocyte Interactions Paratope Hotspots (GLIPH). Cytomegalovirus (CMV)-IgG was measured an additional 113 93 HCs. Regulatory T (Tregs) flow cytometry. Results diversity all four chains decreased age. TCRα TCRβ higher (P = 0.0015 0.024, respectively), even after age correction. TRAJ56 TRBV4-3 more prevalent than HCs (pcorr 0.027 0.040, respectively). GLIPH consolidated 208,674 clones into 1,294 clusters, among which two candidate clusters identified. The cluster shared HLA-DRB1*04:05-positive (87.5%) predicted to recognize CMV peptides (CMV-TCR). Severity Score (MSSS) lower CMV-TCR those without 0.037). CMV-IgG-positivity associated MSSS HLA-DRB1*04:05 carriers 0.0053). individuals demonstrated CMV-IgG titers HLA-DRB1*04:05-negative 0.017). CMV-IgG-positive had Tregs CMV-IgG-negative 0.054). Interpretation High TCRα/TCRβ regardless age, is characteristic MS. Association CMV-recognizing mild disability indicates CMV's protective role