Specific roles of each TCR hemichain in generating functional chain-centric TCR.
Specific roles of each TCR hemichain in generating functional chain-centric TCR.
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DOI：
10.4049/jimmunol.1401717
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发表时间：
2015-04-01
期刊：
影响因子：
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通讯作者：
Hirano N
中科院分区：
文献类型：
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作者：
Nakatsugawa M;Yamashita Y;Ochi T;Tanaka S;Chamoto K;Guo T;Butler MO;Hirano N
T细胞受体(TCR)α和β链协同识别肽- mhc （pMHC）复合物。研究表明，“链中心”TCR半链本身可以决定mhc限制性抗原特异性，而不需要配对的TCR反链的主要贡献。然而，关于以链为中心的链及其反链、非链为中心的链在决定T细胞贪婪度中的相对贡献和作用，我们所知甚少。我们全面分析了通过将以α链为中心的HLA-A*02:01(A2)/ MART127-35 TCRα，克隆SIG35α转导为A2匹配和未匹配的胸腺后T细胞而产生的胸腺非选择T细胞库。不管它们的HLA-A2阳性与否，有相当一部分用SIG35α转导的外周T细胞获得了A2/ MART127-35的反应性。虽然生成的A2/ mart127 - 35特异性T细胞使用各种TRBV基因，但TRBV27以bbb102高度多样化和独特的克隆型CDR3β序列为主。用A2/ MART127-35 TRBV27 TCRβ基因和SIG35α单独重组的T细胞具有宽范围（bbb2对数数量级）的亲和性。大约一半具有比表达克隆DMF5的T细胞更高的亲和力，DMF5是一种天然存在的A2/ MART127-35 TCR，具有最高的亲和力之一。重要的是，类似的发现在其他自体抗原中得到了概括。我们的研究结果表明，尽管以链为中心的TCR半链决定抗原特异性，但配对的反链可以在不影响抗原特异性的情况下在很宽的范围内（bbb20 - 2个对数数量级）调节亲和力。利用TCR链的中心性可以产生胸腺非选择性抗原特异性T细胞库，该库可用于分离高亲和性抗肿瘤T细胞及其独特编码的TCR，由于耐受性，很少在外周发现。
T cell receptor (TCR)α and β chains cooperatively recognize peptide-MHC (pMHC) complexes. It has been shown that a ‘chain-centric’ TCR hemichain can, by itself, dictate MHC-restricted antigen specificity without requiring major contributions from the paired TCR counterchain. Little is known, however, regarding the relative contributions and roles of chain-centric and its counter, non-chain-centric hemichains in determining T cell avidity. We comprehensively analyzed a thymically unselected T cell repertoire generated by transducing the α chain-centric HLA-A*02:01(A2)/MART127–35 TCRα, clone SIG35α, into A2-matched and unmatched post-thymic T cells. Regardless of their HLA-A2 positivity, a substantial subset of peripheral T cells transduced with SIG35α gained reactivity for A2/MART127–35. While the generated A2/MART127–35-specific T cells used various TRBV genes, TRBV27 predominated with >102 highly diverse and unique clonotypic CDR3β sequences. T cells individually reconstituted with various A2/MART127–35 TRBV27 TCRβ genes along with SIG35α possessed a wide range (>2 log orders) of avidity. Approximately half possessed avidity higher than T cells expressing clone DMF5, a naturally occurring A2/MART127–35 TCR with one of the highest affinities. Importantly, similar findings were recapitulated with other self-antigens. Our results indicate that, although a chain-centric TCR hemichain determines antigen specificity, the paired counterchain can regulate avidity over a broad range (>2 log orders) without compromising antigen specificity. TCR chain centricity can be exploited to generate a thymically unselected antigen-specific T cell repertoire, which can be used to isolate high avidity antitumor T cells and their uniquely encoded TCRs rarely found in the periphery due to tolerance.