Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease
Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease
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DOI：
10.1016/j.immuni.2012.07.013
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发表时间：
2012-10-19
期刊：
影响因子：
32.4
通讯作者：
Rossjohn, Jamie
中科院分区：
文献类型：
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作者：
Broughton, Sophie E.;Petersen, Jan;Rossjohn, Jamie
乳糜泻是一种人类白细胞抗原（HLA）-DQ 2和/或DQ 8相关的T细胞介导的疾病，由膳食麸质诱导。尽管已经确定了谷蛋白肽如何结合HLA-DQ 8和HLA-DQ 2，但尚不清楚这种肽-HLA复合物如何被T细胞受体（TCR）接合，这是一种触发疾病病理的识别事件。我们表明，偏向TCR的使用（TRBV 9 *01）支持识别HLA-DQ 8-α-I-麦醇溶蛋白。原型TRBV 9 *01-TCR-HLA-DQ 8-α-I-麦胶蛋白复合物的结构显示TCR在HLADQ 8-α-I-麦胶蛋白上方集中停靠，其中所有互补决定区-β（CDR β）环与麦胶蛋白肽相互作用。TRBV 9 *01-TCR-HLA-DQ 8-α-I-麦胶蛋白界面处的突变为V β偏好提供了有力的基础。此外，CDR 3多样性解释了TRBV 9 *01（+）TCR在各种脱酰胺状态下对麦胶蛋白表位表现出不同的反应性。因此，偏向性TCR使用是DQ 8介导的乳糜泻发病机制中的重要因素。
Celiac disease is a human leukocyte antigen (HLA)-DQ2- and/or DQ8-associated T cell-mediated disorder that is induced by dietary gluten. Although it is established how gluten peptides bind HLA-DQ8 and HLA-DQ2, it is unclear how such peptide-HLA complexes are engaged by the T cell receptor (TCR), a recognition event that triggers disease pathology. We show that biased TCR usage (TRBV9*01) underpins the recognition of HLA-DQ8-alpha-I-gliadin. The structure of a prototypical TRBV9*01-TCR-HLA-DQ8-alpha-I-gliadin complex shows that the TCR docks centrally above HLADQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDR beta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9*01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the V beta bias. Moreover, CDR3 diversity accounts for TRBV9*01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.