PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice
PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice
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DOI：
10.1073/pnas.0710951105
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发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Yoshida, Taku;Jiang, Fang;Okazaki, Taku
尽管许多自身免疫性疾病与特定的HLA/H-2单倍型相关，但特定HLA/H-2单倍型提供自身免疫性易感性的机制仍然是谜。在此，我们分析了糖尿病相关（H-2（g7））和抗糖尿病（H-2（B））H-2单倍型在缺乏程序性细胞死亡-1（PD-1，Pdcd 1）的NOD小鼠中的作用，PD-1是一种独特的1型糖尿病模型，可使疾病完全消退和快速发作。NOD-H2（B/B）Pdcd 1（-/-）小鼠完全免于糖尿病，证实了即使在不存在PD-1的情况下，H-2（g7）对于糖尿病也是必不可少的。然而，NOD-H2（B/B）Pdcd 1（-/-）小鼠在包括外周神经、胃和外分泌组织在内的多种组织中发生了自身免疫性炎症，表明在H-2（B）的背景下产生了自身反应性T细胞。这些自身反应性T细胞仅在不存在PD-1的情况下损伤靶组织，证实PD-1缺乏通过降低T细胞活化的阈值来揭示菌株的隐藏的自身免疫易感性。转移实验表明，CD 4 T细胞是神经炎的效应细胞，神经浸润的CD 4 T细胞强烈偏向Th 1。有趣的是，在H-2（g7）的背景下也产生了神经突原性T细胞，这与糖尿病对H-2（g7）的严格要求形成鲜明对比。此外，60%的NOD-H2（B/g7）Pdcd 1（-/-）小鼠发生糖尿病，表明H-2（B）不主要抑制糖尿病，H-2（g7）以剂量依赖性方式诱导糖尿病。
Although many autoimmune diseases are associated with particular HLA/H-2 haplotypes, the mechanisms through which specific HLA/H-2 haplotypes afford autoimmune susceptibility remain enigmatic. Here, we analyzed the effects of the diabetes-associated (H-2(g7)) and an antidiabetogenic (H-2(b)) H-2 haplotypes in NOD mice deficient for programmed cell death-1 (PD-1, Pdcd1), a unique model of type 1 diabetes that confers complete penetrance and rapid onset of the disease. NOD-H2(b/b)Pdcd1(-/-) mice were completely protected from diabetes, confirming that H-2(g7) is indispensable for diabetes even in the absence of PD-1. However, NOD-H2(b/b)Pdcd1(-/-) mice developed autoimmune inflammation in multiple tissues including peripheral nerves, stomachs, and exocrine tissues, demonstrating that autoreactive T cells are generated in the context of H-2(b). These autoreactive T cells damaged target tissues only in the absence of PD-1, confirming that PD-1 deficiency unravels the hidden autoimmune susceptibility of the strain by reducing the threshold of T cell activation. Transfer experiments revealed that CD4 T cells are the effector cells of neuritis, and nerve-infiltrating CD4 T cells are strongly deviated toward Th1. Interestingly, neuritogenic T cells were also generated in the context of H-2(g7), in sharp contrast to the strict requirement of H-2(g7) for diabetes. In addition, 60% of the NOD-H2(b/g7)Pdcd1(-/-) mice developed diabetes, suggesting that H-2(b) does not dominantly suppress diabetes and that H-2(g7) induces diabetes in a dose-dependent fashion.