サイトウ　ミネキ   Mineki Saito   齊藤　峰輝    所属   川崎医科大学  医学部 基礎医学　微生物学    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	High TCR Degeneracy Enhances Antiviral Efficacy of HTLV-1-Specific CTLs by Targeting Variant Viruses in HAM Patients.
掲載誌名	正式名：International journal of molecular sciences 略　 称：Int J Mol Sci ISSNコード：14220067/14220067
掲載区分	国外
巻・号・頁	26(14)
著者・共著者	Ryuji Kubota, Kousuke Hanada, Mineki Saito, Mika Dozono, Satoshi Nozuma, Hiroshi Takashima
発行年月	2025/07/10
概要	T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which recognize peptide-MHC class I complexes via TCRs, play a critical role in the immune response against viral infections. However, the extent to which TCR degeneracy within a population of virus-specific CTLs contributes to effective viral control remains poorly understood. In this study, we investigated the magnitude and functional relevance of TCR degeneracy in CTLs targeting an immunodominant epitope of human T-cell leukemia virus type 1 (HTLV-1) in patients with HTLV-1-associated myelopathy (HAM). Using peripheral blood mononuclear cells (PBMCs) from these patients, we quantified TCR degeneracy at the population level by comparing CTL responses to a panel of APLs with responses to the cognate epitope. Our findings demonstrated that increased TCR degeneracy, particularly at the primary TCR contact residue at position 5 of the antigen, was inversely correlated with HTLV-1 proviral load (p = 0.038, R = -0.40), despite similar functional avidity across patient-derived CTLs. Viral sequencing further revealed that CTLs with high TCR degeneracy exerted stronger selective pressure on the virus, as indicated by a higher frequency of nonsynonymous substitutions within the epitope-encoding region in patients with highly degenerate TCR repertoires. Moreover, TCR degeneracy was positively correlated with the recognition rate of epitope variants (p = 0.018, R = 0.76), suggesting that CTLs with high TCR degeneracy exhibited enhanced recognition of naturally occurring epitope variants compared to those with low TCR degeneracy. Taken together, these results suggest that virus-specific CTLs with high TCR degeneracy possess superior antiviral capa
DOI	10.3390/ijms26146602
PMID	40724852