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首页> 外文期刊>Journal of Molecular Biology >Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.
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Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.

机译：肿瘤相关的MHC II类限制性磷酸肽呈递给CD4 + T细胞的结构基础。

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摘要

Dysregulated protein phosphorylation is a hallmark of malignant transformation. Transformation can generate major histocompatibility complex (MHC)-bound phosphopeptides that are differentially displayed on tumor cells for specific recognition by T cells. To understand how phosphorylation alters the antigenic identity of self-peptides and how MHC class II molecules present phosphopeptides for CD4(+) T-cell recognition, we determined the crystal structure of a phosphopeptide derived from melanoma antigen recognized by T cells-1 (pMART-1), selectively expressed by human melanomas, in complex with HLA-DR1. The structure revealed that the phosphate moiety attached to the serine residue at position P5 of pMART-1 is available for direct interactions with T-cell receptor (TCR) and that the peptide N-terminus adopts an unusual conformation orienting it toward TCR. This structure, combined with measurements of peptide affinity for HLA-DR1 and of peptide-MHC recognition by pMART-1-specific T cells, suggests that TCR recognition is focused on the N-terminal portion of pMART-1. This recognition mode appears to be distinct from that of foreign antigen complexes but is remarkably reminiscent of the way autoreactive TCRs engage self- or altered self-peptides, consistent with the tolerogenic nature of tumor-host immune interactions.
机译：蛋白质磷酸化失调是恶性转化的标志。转化可产生主要的组织相容性复合物（MHC）结合的磷酸肽，该肽在肿瘤细胞上差异展示，可被T细胞特异性识别。为了了解磷酸化如何改变自身肽的抗原性以及MHC II类分子如何为CD4（+）T细胞识别提供磷酸肽，我们确定了由T细胞-1（pMART）识别的黑色素瘤抗原衍生的磷酸肽的晶体结构-1），由人黑素瘤选择性表达，与HLA-DR1复合。该结构表明，附着在pMART-1位置P5丝氨酸残基上的磷酸部分可用于与T细胞受体（TCR）直接相互作用，而肽N端采用一种不寻常的构象，使其朝向TCR。这种结构与对HLA-DR1的肽亲和力和pMART-1特异性T细胞对肽-MHC识别的测量结果相结合，表明TCR识别集中在pMART-1的N端部分。这种识别方式似乎与外源抗原复合物的识别方式不同，但明显使人联想到自身反应性TCR结合自身或改变的自身肽的方式，这与肿瘤-宿主免疫相互作用的耐受性相一致。

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