A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen.
A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen.
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DOI：
10.1074/jbc.m115.707414
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发表时间：
2016-04-22
期刊：
影响因子：
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通讯作者：
Cole DK
中科院分区：
文献类型：
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作者：
Bianchi V;Bulek A;Fuller A;Lloyd A;Attaf M;Rizkallah PJ;Dolton G;Sewell AK;Cole DK
人CD 8+细胞毒性T淋巴细胞可通过特异性识别HLA限制性肽介导黑色素瘤的肿瘤消退。由于大多数抗癌T细胞受体（TCR）的亲和力相对较弱，因此越来越强调用改变的肽配体免疫黑素瘤患者，以诱导能够打破对这些自身抗原的耐受性的强抗肿瘤免疫。然而，先前的研究表明，这些免疫原性设计肽并不总是有效的。黑素细胞分化蛋白，糖蛋白100（gp 100），编码天然加工的表位，其是黑色素瘤免疫疗法，特别是基于肽的疫苗的有吸引力的靶标。先前的研究已经表明，肽残基Glu 3处的取代对多克隆T细胞应答具有广泛的负面影响。在这里，我们描述了与该gp 100表位复合的天然同源TCR的第一原子结构，并强调了相互作用的相对高的亲和力。跨gp 100280 -288肽进行的丙氨酸扫描诱变显示Glu 3对于TCR结合至关重要。出乎意料的是，结构分析表明Glu 3 → Ala取代导致分子开关传递到相邻残基，废除TCR结合和T细胞识别。这些发现有助于阐明黑色素瘤反应期间T细胞识别gp 100的机制，并可指导疫苗接种用改变肽的开发。
Human CD8+ cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu3 have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100280–288 peptide showed that Glu3 was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu3 → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination.