GAD65-Specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes
GAD65-Specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes
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DOI：
10.2337/diabetes.53.8.1987
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发表时间：
2004-08-01
期刊：
影响因子：
7.7
通讯作者：
Nepom, GT
中科院分区：
文献类型：
--
作者：
Reijonen, H;Mallone, R;Nepom, GT
胸腺发育过程中自身反应性T细胞的阴性选择，沿着外周淋巴细胞中活化诱导的细胞死亡，旨在限制自身反应性T细胞的扩增和持续。然而，在1型糖尿病患者和高危受试者中，自身反应性T细胞都存在。通过使用MHC II类四聚体探测从1型糖尿病患者分离的GAD 65反应性T细胞克隆的T细胞受体（TcR）特异性和亲合力，我们鉴定了外周血中高亲合力CD 4（+）T细胞，其与针对相同GAD 65表位特异性的低亲合力细胞共存。观察到多种细胞因子模式，甚至在具有高MHC-肽亲合力的T细胞中也是如此，并且克隆利用偏向于两种组合的TcR基因集，即Valpha 12-beta5.1和Valpha 17-Vbeta 4。这些高亲合力TcR的存在表明未能删除自身反应性T细胞，其可能是在1型糖尿病进展期间响应于自身抗原暴露而产生的寡克隆扩增。
Negative selection of self-reactive T-cells during thymic development, along with activation-induced cell death in peripheral lymphocytes, is designed to limit the expansion and persistence of autoreactive T-cells. Autoreactive T-cells are nevertheless present, both in patients with type 1 diabetes and in at-risk subjects. By using MHC class II tetramers to probe the T-cell receptor (TcR) specificity and avidity of GAD65 reactive T-cell clones isolated from patients with type 1 diabetes, we identified high-avidity CD4(+) T-cells in peripheral blood, coexisting with low-avidity cells directed to the same GAD65 epitope specificity. A variety of cytokine patterns was observed, even among T-cells with high MHC-peptide avidity, and the clones utilize a biased set of TcR genes that favor two combinations, Valpha12-beta5.1 and Valpha17-Vbeta4. Presence of these high-avidity TcRs indicates a failure to delete autoreactive T-cells that likely arise from oligoclonal expansion in response to autoantigen exposure during the progression of type 1 diabetes.