Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
J Exp Med. 2011 Nov 21;208(12):2375-83. doi: 10.1084/jem.20111502. Epub 2011 Nov 7.
In nonobese diabetic (NOD) mice, two sets of autoreactive CD4(+) T cells recognize the B:9-23 segment of the insulin B chain. One set, type A, recognizes insulin presented by antigen-presenting cells (APCs). These T cells are highly deleted in the thymus. The second set, type B, does not recognize insulin protein but reacts with soluble B chain peptide. This set is not deleted in the thymus but is activated in the islets of Langerhans. In this study, we examine the specificity of these two types of T cells. The protein-reactive set recognizes the stretch of residues 13-21 of the insulin B chain. The set reactive to peptide only recognizes the stretch from residues 12-20. A single amino acid shift of the B chain peptide bound to I-A(g7) determines whether T cells recognize peptides generated by the processing of insulin, and consequently their escape from thymic purging. Biochemical experiments indicate that peptides bound in the 13-21 register interact more favorably with I-A(g7) than peptides that bind in the 12-20 register. Thus, self-reactive T cells can become pathogenic in the target organ where high concentrations of antigen and/or differences in intracellular processing present peptides in registers distinct from those found in the thymus.
在非肥胖型糖尿病（NOD）小鼠中，两组自身反应性 CD4(+) T 细胞识别胰岛素 B 链的 B:9-23 片段。一组，即 A 型，识别抗原呈递细胞（APC）呈递的胰岛素。这些 T 细胞在胸腺中高度缺失。第二组，B 型，不识别胰岛素蛋白，但与可溶性 B 链肽反应。该组在胸腺中未被删除，但在胰岛中被激活。在这项研究中，我们检查了这两种类型的 T 细胞的特异性。蛋白反应性组识别胰岛素 B 链残基 13-21 的延伸。仅对肽反应的组识别残基 12-20 的延伸。与 I-A(g7) 结合的 B 链肽的单个氨基酸移位决定了 T 细胞是否识别由胰岛素加工产生的肽，从而决定了它们是否逃避胸腺清除。生化实验表明，与结合在 12-20 位的肽相比，结合在 13-21 位的肽与 I-A(g7) 相互作用更有利。因此，自身反应性 T 细胞可以在靶器官中成为致病性的，在靶器官中，高浓度的抗原和/或细胞内加工的差异会导致肽出现在与胸腺中不同的区域。
