St. Vincent's Institute, Fitzroy, Victoria 3065, Australia.
J Immunol. 2011 Aug 15;187(4):1702-12. doi: 10.4049/jimmunol.1100511. Epub 2011 Jul 6.
TNF has been implicated in the pathogenesis of type 1 diabetes. When administered early in life, TNF accelerates and increases diabetes in NOD mice. However, when administered late, TNF decreases diabetes incidence and delays onset. TNFR1-deficient NOD mice were fully protected from diabetes and only showed mild peri-insulitis. To further dissect how TNFR1 deficiency affects type 1 diabetes, these mice were crossed to β cell-specific, highly diabetogenic TCR transgenic I-A(g7)-restricted NOD4.1 mice and Kd-restricted NOD8.3 mice. TNFR1-deficient NOD4.1 and NOD8.3 mice were protected from diabetes and had significantly less insulitis compared with wild type NOD4.1 and NOD8.3 controls. Diabetic NOD4.1 mice rejected TNFR1-deficient islet grafts as efficiently as control islets, confirming that TNFR1 signaling is not directly required for β cell destruction. Flow cytometric analysis showed a significant increase in the number of CD4(+)CD25(+)Foxp3(+) T regulatory cells in TNFR1-deficient mice. TNFR1-deficient T regulatory cells were functionally better at suppressing effector cells than were wild type T regulatory cells both in vitro and in vivo. This study suggests that blocking TNF signaling may be beneficial in increasing the function of T regulatory cells and suppression of type 1 diabetes.
肿瘤坏死因子（TNF）在 1 型糖尿病的发病机制中起作用。在生命早期给予 TNF 会加速和增加 NOD 小鼠的糖尿病。然而，晚期给予 TNF 会降低糖尿病的发生率并延迟发病。TNFR1 缺陷型 NOD 小鼠完全免受糖尿病的影响，仅表现出轻度胰岛炎。为了进一步剖析 TNFR1 缺陷如何影响 1 型糖尿病，将这些小鼠与β细胞特异性、高度致糖尿病 TCR 转基因 I-A(g7)-限制性 NOD4.1 小鼠和 Kd 限制性 NOD8.3 小鼠进行杂交。TNFR1 缺陷型 NOD4.1 和 NOD8.3 小鼠免受糖尿病的影响，与野生型 NOD4.1 和 NOD8.3 对照相比，胰岛炎明显减少。糖尿病 NOD4.1 小鼠排斥 TNFR1 缺陷型胰岛移植物的效率与对照胰岛一样高，证实 TNFR1 信号传导不是β细胞破坏的直接需要。流式细胞术分析显示 TNFR1 缺陷型小鼠中 CD4(+)CD25(+)Foxp3(+)T 调节细胞的数量显著增加。TNFR1 缺陷型 T 调节细胞在体外和体内均比野生型 T 调节细胞在抑制效应细胞方面具有更好的功能。这项研究表明，阻断 TNF 信号可能有益于增加 T 调节细胞的功能并抑制 1 型糖尿病。
