Distinct sets of αβ TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues
Distinct sets of αβ TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues
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DOI：
10.1073/pnas.0807954105
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发表时间：
2008-09-30
影响因子：
11.1
通讯作者：
Rufer, Nathalie
中科院分区：
文献类型：
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作者：
Derre, Laurent;Bruyninx, Marc;Rufer, Nathalie
针对人类癌症的自然获得性免疫反应通常包括针对癌症睾丸抗原NY-ESO-1的CD8(+)T细胞。在这里，我们研究了来自5例黑色素瘤患者的605个人类白细胞抗原-A*0201/NY-ESO-1(157-165)特异性CD8T细胞克隆的T细胞受体(TCR)一级结构和功能。我们发现，很大一部分肿瘤反应性T细胞优先使用TCRAV3S1/BV8S2链，这两条链上的CDR3氨基酸基序和长度都非常保守。所有剩余的T细胞克隆属于另外两个表达BV1或BV13 TCR的集合，与具有高度不同的VJ用途、CDR3氨基酸序列和长度的阿尔法链相关。然而，所有T细胞克隆型都以相似的功能亲和力识别肿瘤抗原。两个残基Met-160和Trp-161位于NY-ESO-1(157-165)肽的中间区域，对大多数T细胞克隆型的识别至关重要。综上所述，我们的数据表明，属于三个不同集合(AVX/BV1，AV3/BV8，AVX/BV13)的大量α-βTCR以相同的抗原敏感性结合pMHC，并识别相同的肽基序。最后，这种对自身抗原识别的深入研究表明，在一定程度上，类似的生物物理机制塑造了针对外来和自身抗原的TCR谱系。
Naturally acquired immune responses against human cancers often include CD8(+) T cells specific for the cancer testis antigen NY-ESO-1. Here, we studied T cell receptor (TCR) primary structure and function of 605 HLA-A*0201/NY-ESO-1(157-165)-specific CD8 T cell clones derived from five melanoma patients. We show that an important proportion of tumor-reactive T cells preferentially use TCR AV3S1/BV8S2 chains, with remarkably conserved CDR3 amino acid motifs and lengths in both chains. All remaining T cell clones belong to two additional sets expressing BV1 or BV13 TCRs, associated with alpha-chains with highly diverse VJ usage, CDR3 amino acid sequence, and length. Yet, all T cell clonotypes recognize tumor antigen with similar functional avidity. Two residues, Met-160 and Trp-161, located in the middle region of the NY-ESO-1(157-165) peptide, are critical for recognition by most of the T cell clonotypes. Collectively, our data show that a large number of alpha beta TCRs, belonging to three distinct sets (AVx/BV1, AV3/BV8, AVx/BV13) bind pMHC with equal antigen sensitivity and recognize the same peptide motif. Finally, this in-depth study of recognition of a self-antigen suggests that in part similar biophysical mechanisms shape TCR repertoires toward foreign and self-antigens.