Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice
Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice
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DOI：
10.1172/jci38503
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发表时间：
2009-06-01
影响因子：
15.9
通讯作者：
von Herrath, Matthias G.
中科院分区：
文献类型：
--
作者：
Filippi, Christophe M.;Estes, Elizabeth A.;von Herrath, Matthias G.
1型糖尿病（T1 D）是一种自身免疫性疾病，由产生胰岛素的β细胞破坏引起。病毒感染诱导免疫反应，可以破坏P细胞并促进T1 D或另一方面防止疾病的发展。然而，病毒感染在T1 D中的相反作用还没有被机械地理解。我们在这里报告说，不对P细胞造成损害的病毒通过触发免疫调节机制提供了对T1 D的保护。用科萨基病毒B3或淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染糖尿病前期NOD小鼠可延迟糖尿病发作并降低发病率。延迟T1 D发作是由于淋巴细胞上程序性细胞死亡-1配体1（PD-L1）的瞬时上调，这阻止了表达程序性细胞死亡-1（PD-1）的致糖尿病CD 8（+）T细胞的扩增。T1 D发病率的降低是由活化的CD 4（+）CD 25（+）T细胞数量增加引起的，T细胞产生TGF-β并维持长期耐受性。PD-L1和CD 4（+）CD 25（+）T淋巴细胞之间的协同作用导致了对T1 D的完全保护。我们的研究结果提供了我们认为是新的机制洞察病毒在T1 D中的作用，应该是有价值的人类前瞻性研究。
Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing beta cells. Viral infections induce immune responses that can damage P cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on P cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death-1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic CD8(+)T cells expressing programmed cell death-1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated CD4(+)CD25(+) Tregs, which produced TGF-beta and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and CD4(+)CD25(+) Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans.