T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease
T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease
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DOI：
10.1038/nsmb.2817
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发表时间：
2014-05-01
影响因子：
16.8
通讯作者：
Rossjohn, Jamie
中科院分区：
文献类型：
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作者：
Petersen, Jan;Montserrat, Veronica;Rossjohn, Jamie
乳糜泻是一种由膳食面筋引起的T细胞介导的疾病，谷蛋白的一种成分是醇溶蛋白。95%的乳糜泻患者携带人类白细胞抗原-DQ2基因。在这里，我们确定了针对小麦醇溶蛋白两个表位的患者来源的T细胞克隆的T细胞受体(TCR)的使用和精细特异性。我们确定了四个针对这些表位的不同偏向的TCR的三元结构。所有三个针对DQ2.5glia-α2的TCR都位于HLA-DQ2的中央对接，这与突变和亲和力测量一起为TCR的偏向使用提供了基础。CDR3测试环中的一个非生殖系编码的精氨酸残基在这个共同的对接足迹中起着关键作用。尽管DQ2.5-Glya-Alpha a和DQ2.5-Glya-Alpha 2的TCR对接相似，但它们与各自的醇溶蛋白决定簇的相互作用明显不同，从而为表位特异性提供了基础。
Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-alpha 1a and DQ2.5-glia-alpha 2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5glia-alpha 2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3 beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha 1a a and DQ2.5-glia-alpha 2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.