不均衡的TCR链配对约束决定表位识别

不均衡的TCR链配对约束决定表位识别

作者： 小柯机器人 发布时间：2026/9/5 17:35:06

本期文章：《科学》：Volume 393 Issue 6815

2026年9月3日，美国弗雷德·哈钦森癌症中心Anastasia A. Minervina等科学家在《科学》（Science）发表研究，揭示了TCR链配对的不均衡约束如何决定表位识别。

独立重排的T细胞受体（TCR）α链和β链的组合配对是多样化TCR库的核心。尽管一条链中的序列基序与表位识别相关，但单条链在多大程度上决定特异性仍不清楚。在此，研究人员通过将单条链与数十万个伙伴强制配对，系统测试了TCR链配对约束。尽管大多数链能稳定配对，但表位特异性的保留是罕见的且高度可变，兼容伙伴的频率范围从约10%到低于0.1%。该方法在10个表位中鉴定出超过70,000个表位特异性TCR。这项工作阐明了TCR链的不同贡献，凸显了单链数据的局限性，并为优化TCR-肽-主要组织相容性复合体特异性推断提供了实验和分析框架。

附：英文原文

Title: Uneven TCR chain pairing constraints govern epitope recognition

Author: Anastasia A. Minervina, Mikhail V. Pogorelyy, Koshlan Mayer-Blackwell, Ricky Tirtakusuma, Stefan A. Schattgen, Andrew Fiore-Gartland, Aleksandra M. Walczak, Thierry Mora, Philip Bradley, Paul G. Thomas

Issue&Volume: 2026-09-03

Abstract: Combinatorial pairing of independently recombined T cell receptor (TCR) α- and β-chains is central to diversifying the TCR repertoire. Although sequence motifs in one chain correlate with epitope recognition, the extent to which a single chain dictates specificity remains unclear. Here, we systematically tested TCR chain coupling constraints by enforcing the pairing of individual chains with hundreds of thousands of partners. Although most chains paired stably, the preservation of epitope specificity was rare and highly variable, with the frequency of compatible partners ranging from ~10 to <0.1%. This approach identified >70,000 epitope-specific TCRs across 10 epitopes. Our work illuminates the distinct contributions of TCR chains, highlights the limitations of single-chain data, and provides an experimental and analytical framework for refining TCR-peptide-major histocompatibility complex specificity inference.

DOI: 10.1126/science.adx3863

Source: https://www.science.org/doi/10.1126/science.adx3863

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