Diabetes Research Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales, U.K.
Section of Endocrinology, School of Medicine, Yale University, New Haven, CT.
Diabetes. 2019 May;68(5):1002-1013. doi: 10.2337/db18-0487. Epub 2019 Feb 22.
Insulin is a major autoantigen in type 1 diabetes, targeted by both CD8 and CD4 T cells. We studied an insulin-reactive T-cell receptor (TCR) α-chain transgenic NOD mouse on a TCRCα and proinsulin 2 (PI2)-deficient background, designated as NOD mice. These mice develop a low incidence of autoimmune diabetes. To test the role of gut microbiota on diabetes development in this model system, we treated the NOD mice with enrofloxacin, a broad-spectrum antibiotic. The treatment led to male mice developing accelerated diabetes. We found that enrofloxacin increased the frequency of the insulin-reactive CD8+ T cells and activated the cells in the Peyer's patches and pancreatic lymph nodes, together with induction of immunological effects on the antigen-presenting cell populations. The composition of gut microbiota differed between the enrofloxacin-treated and untreated mice and also between the enrofloxacin-treated mice that developed diabetes compared with those that remained normoglycemic. Our results provide evidence that the composition of the gut microbiota is important for determining the expansion and activation of insulin-reactive CD8+ T cells.
胰岛素是 1 型糖尿病的主要自身抗原，可被 CD8 和 CD4 T 细胞靶向。我们研究了一种胰岛素反应性 T 细胞受体（TCR）α链转基因 NOD 小鼠，该小鼠在 TCRCα 和前胰岛素 2（PI2）缺陷背景下，被指定为 NOD 小鼠。这些小鼠发生自身免疫性糖尿病的发生率较低。为了测试肠道微生物群在该模型系统中对糖尿病发展的作用，我们用广谱抗生素恩诺沙星治疗 NOD 小鼠。该治疗导致雄性小鼠加速发生糖尿病。我们发现恩诺沙星增加了胰岛素反应性 CD8+T 细胞的频率，并激活了派伊尔斑和胰腺淋巴结中的细胞，同时对抗原呈递细胞群体产生了免疫效应。接受恩诺沙星治疗的小鼠与未接受治疗的小鼠以及发生糖尿病的恩诺沙星治疗小鼠与保持正常血糖的恩诺沙星治疗小鼠之间的肠道微生物群组成存在差异。我们的结果提供了证据，表明肠道微生物群的组成对于确定胰岛素反应性 CD8+T 细胞的扩增和激活很重要。
