Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules.
Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules.
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DOI：
10.4049/jimmunol.1901079
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发表时间：
2020-05-01
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--
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中科院分区：
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1型糖尿病（T1 D）是一种T细胞介导的自身免疫性疾病，其中胰腺内产生胰岛素的β细胞被破坏。鉴定β细胞反应性T细胞的靶抗原和表位对于理解T1 D发病机制和合理开发针对该疾病的抗原特异性免疫疗法都是重要的。一些研究表明，胰岛素原是T1 D的早期和完整的靶向自身抗原。然而，人CD 4 + T细胞识别的胰岛素原表位尚未得到全面表征。使用基于染料稀释的T细胞克隆方法，我们从17名携带高危DR 3-DQ 2和/或DR 4-DQ 8 HLA II类单倍型的个体的外周血中产生并表征了24个独特的胰岛素原特异性CD 4 + T细胞克隆。一些克隆识别先前报道的胰岛素原C肽（C25-35）或A链（A1-15）内的DR 4限制性表位。然而，我们还表征了B链（B16-27和B22-C3）和C肽（C25-35）内的新型DR 3限制性表位。此外，我们确定了新的DQ 2限制性表位的B链和几个DQ 2或DQ 8限制性表位的C-肽的C-末端区域内的部分重叠与以前报道的DQ限制性表位。DQ 2限制性表位中的两个，B18-26和C22-33，被证明是从完整的人胰岛素原天然加工的。最后，我们观察到与脾样品相比，在胰腺淋巴结样品中与胰岛素原特异性T细胞克隆的TCR序列匹配的CDR 3序列的频率更高。总之，我们证实了几个先前报道的表位，但也确定了新的表位内胰岛素原，这是由HLA II类分子与T1 D的风险。
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease in which the insulin-producing β-cells within the pancreas are destroyed. Identification of target antigens and epitopes of the β-cell-reactive T cells is important both for the understanding T1D pathogenesis and for the rational development of antigen-specific immunotherapies for the disease. Several studies suggest that proinsulin is an early and integral target autoantigen in T1D. However, proinsulin epitopes recognized by human CD4+ T cells have not been comprehensively characterized. Using a dye-dilution based T-cell cloning method, we generated and characterized 24 unique proinsulin-specific CD4+ T-cell clones from the peripheral blood of 17 individuals who carry the high-risk DR3-DQ2 and/or DR4-DQ8 HLA class II haplotypes. Some of the clones recognized previously reported DR4-restricted epitopes within the C-peptide (C25-35) or A-chain (A1-15) of proinsulin. However, we also characterized novel DR3-restricted epitopes within both the B-chain (B16-27 and B22-C3) and C-peptide (C25-35). Moreover, we identified novel DQ2-restricted epitopes within the B-chain and several DQ2- or DQ8-restricted epitopes within the C-terminal region of C-peptide that partially overlap with previously reported DQ-restricted epitopes. Two of the DQ2-restricted epitopes, B18-26 and C22-33, were shown to be naturally processed from whole human proinsulin. Finally, we observed a higher frequency of CDR3 sequences matching the TCR sequences of the proinsulin-specific T-cell clones in pancreatic lymph node samples compared to spleen samples. In conclusion, we confirmed several previously reported epitopes but also identified novel epitopes within proinsulin, which are presented by HLA class II molecules associated with T1D risk.
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影响因子：
46.9
作者：
Han, Arnold;Glanville, Jacob;Hansmann, Leo;Davis, Mark M.
通讯作者：
Davis, Mark M.
影响因子：
82.9
作者：
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影响因子：
7.7
作者：
Ilonen, Jorma;Hammais, Anna;Knip, Mikael
通讯作者：
Knip, Mikael
影响因子：
64.8
作者：
Kent, SC;Chen, YH;Hafler, DA
通讯作者：
Hafler, DA
DOI：
10.1073/pnas.95.7.3833
发表时间：
1998-03-31
影响因子：
11.1
作者：
Congia, M;Patel, S;Sonderstrup, G
通讯作者：
Sonderstrup, G