A novel population of human melanoma-specific CD8 T cells recognizes Melan-AMART-1 immunodominant nonapeptide but not the corresponding decapeptide
A novel population of human melanoma-specific CD8 T cells recognizes Melan-AMART-1 immunodominant nonapeptide but not the corresponding decapeptide
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DOI：
10.4049/jimmunol.179.11.7635
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Speiser, Daniel E.
中科院分区：
文献类型：
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作者：
Derre, Laurent;Ferber, Mathias;Speiser, Daniel E.
特异于免疫显性人肿瘤Ag Melan-A（MART-1）的HLA-A2限制性溶细胞T细胞可以通过识别两种天然存在的抗原变体，即，Melan-A九聚体AAGIGILTV和十聚体EAAGIGILTV肽。先前的几项研究表明，TCR对这两种肽具有高度的交叉反应性。在这项研究中，我们首次描述了一些T细胞克隆是专门的九聚体特异性的，因为它们不被A2/十聚体四聚体标记，并且在内源性呈现时不识别十聚体。用肽进行的功能测定给出了误导性的结果，可能是因为十聚体被外肽酶裂解。有趣的是，非肽特异性T细胞克隆很少是V α 2.1阳性的（19个克隆中仅1个），与十聚体特异性克隆中发现的V α 2.1阳性TCR的已知强偏倚（69个克隆中的59个）相反。分子模拟显示，九肽特异性TCR与十肽形成不利的相互作用，而十肽特异性TCR在十肽的CDR 1 α和谷氨酸（E）之间产生氢键。来自黑色素瘤转移的T细胞的离体分析表明，九聚体和十聚体特异性T细胞在体内富集到相当高的频率，并且代表性克隆显示出有效的肿瘤细胞识别和杀伤。我们的结论是，这两个肽应被视为不同的表位，在分析肿瘤免疫和发展免疫治疗黑色素瘤。
HLA-A2-restricted cytolytic T cells specific for the immunodominant human tumor Ag Melan-A(MART-1) can kill most HLA-matched melanoma cells, through recognition of two naturally occurring antigenic variants, i.e., Melan-A nonamer AAGIGILTV and decamer EAAGIGILTV peptides. Several previous studies have suggested a high degree of TCR cross-reactivity to the two peptides. In this study, we describe for the first time that some T cell clones are exclusively nonamer specific, because they are not labeled by A2/decamer-tetramers and do not recognize the decamer when presented endogenously. Functional assays with peptides gave misleading results, possibly because decamers were cleaved by exopeptidases. Interestingly, nonapeptide-specific T cell clones were rarely V alpha 2.1 positive (only 1 of 19 clones), in contrast to the known strong bias for V alpha 2.1-positive TCRs found in decamer-specific clones (59 of 69 clones). Molecular modeling revealed that nonapeptide-specific TCRs formed unfavorable interactions with the decapeptide, whereas decapeptide-specific TCRs productively created a hydrogen bond between CDR1 alpha and glutamic acid (E) of the decapeptide. Ex vivo analysis of T cells from melanoma metastases demonstrated that both nonamer and decamer-specific T cells were enriched to substantial frequencies in vivo, and representative clones showed efficient tumor cell recognition and killing. We conclude that the two peptides should be regarded as distinct epitopes when analyzing tumor immunity and developing immunotherapy against melanoma.