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

Fumie Hayashi, Noriko Isobe, Jacob Glanville, Takuya Matsushita, Guzailiayi Maimaitijiang, Shoko Fukumoto, Mitsuru Watanabe, Katsuhisa Masaki, Jun ichi Kira

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)163-176
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 2021

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Neurology

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