Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes
Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes
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DOI：
10.1084/jem.20020735
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发表时间：
2002-11-04
影响因子：
15.3
通讯作者：
Goodnow, CC
中科院分区：
文献类型：
--
作者：
Lesage, S;Hartley, SB;Goodnow, CC
1型糖尿病和其他器官特异性自身免疫性疾病通常在人类家族和NOD（非肥胖糖尿病）小鼠的同类品系中聚集在一起，但导致这些疾病的遗传免疫调节缺陷尚不清楚。在这里，我们使用转基因小鼠模型跟踪识别胰岛β细胞中表达的自身抗原的高亲和力CD4 T细胞的命运。具有相同特异性的T细胞识别来自相同胰岛抗原和主要组织相容性复合体（MHC）呈递分子的优势肽，并在自身免疫易感性和耐药遗传背景下进行跟踪。我们发现，非MHC基因从NOD株导致未能删除这些高亲和力自身反应性T细胞在胸腺中的发展过程中，随后自发击穿的CD4细胞耐受胰岛抗原，形成胰岛内生发中心，和高滴度的免疫球蛋白G1自身抗体的生产。在混合骨髓嵌合体动物中，胸腺缺失缺陷是携带糖尿病易感基因的T细胞固有的。这些结果表明，在对器官特异性自身免疫性疾病的遗传易感性中，主要未能审查自身反应性T细胞的禁止克隆，并突出了胸腺耐受机制在器官特异性耐受中的重要性。
Type 1 diabetes and other organ-specific autommume diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet beta cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.