Structures of MART-126/27-35 peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition
Structures of MART-126/27-35 peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition
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DOI：
10.1016/j.jmb.2007.07.025
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发表时间：
2007-10-05
影响因子：
5.6
通讯作者：
Baker, Brian M.
中科院分区：
文献类型：
--
作者：
Borbulevych, Oleg Y.;Insaidoo, Francis K.;Baker, Brian M.
由主要组织相容性复合体（MHC）分子呈递的肽的小的结构变化通常导致免疫原性的大的变化，支持T细胞受体对抗原结构极其敏感的观点。然而，有一些引人注目的例子表明TCR识别结构不同的配体。由此产生的T细胞将如何响应不同或修饰的抗原的不可预测性影响了我们对广泛用作临床疫苗的MART-1/Melan-A蛋白的肽表位和变体的工程化的理解和努力。跨越氨基酸残基26至35的两个重叠表位特别令人感兴趣：在靶向黑素瘤细胞的表面上发现了许多临床上的，尽管只有27 - 35九聚体。在这里，我们表明，26 - 35和27 - 35肽采用显着不同的构象时，结合到HLA-A2。然而，克隆性不同的MART-1（26/27 - 35）-反应性T细胞对这些配体显示出广泛的交叉反应性。然而，与此同时，许多交叉反应性T细胞仍然无法识别具有非常细微结构差异的锚修饰变体。这些二分法的观察结果挑战了我们的想法，即在解决TCR特异性问题时，如何最好地利用未连接肽/MHC复合物的结构信息。我们的研究结果还表明，在基于MART-1 26/27 - 35表位的免疫治疗剂的设计中需要谨慎，因为仅基于结构分析，交叉反应性和选择性都是不可预测的。(c)2007爱思唯尔有限公司保留所有权利。
Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of well as efforts to engineer peptides epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone.(c) 2007 Elsevier Ltd. All rights reserved.