High-affinity islet autoantibodies predict type 1 diabetes in mice and humans and implicate germinal centers (GCs) in type 1 diabetes pathogenesis. T follicular helper (Tfh) cells are increased in type 1 diabetic individuals and alterations in Tfh-like cells in the peripheral blood predicted individual responses to abatacept. Tfh cells support GC responses and depend on the transcriptional repressor BCL6 for their maturation. We therefore hypothesized that CD4-driven deletion of Bcl6 would disrupt essential T-B lymphocyte interactions in GCs to prevent type 1 diabetes. To test this hypothesis, we generated Bcl6fl/fl-CD4.Cre.NOD mice and found they were completely protected against diabetes. Insulitis severity and tertiary lymphoid structure organization were preserved in the pancreas of Bcl6fl/fl-CD4.Cre.NOD mice, which did not show decreases in CD4+, CD8+, and B cell numbers in the pancreas and draining lymph nodes, relative to control Bcl6fl/fl.NOD mice. CD4-driven loss of functional BCL6 resulted in significantly reduced GC B cell and Tfh cell numbers in the pancreatic lymph nodes and pancreas at late prediabetic intervals. Spontaneous anti-insulin autoantibody was blunted in Bcl6fl/fl-CD4.Cre.NOD mice. These data highlight BCL6 as a novel therapeutic target in type 1 diabetes.

中文翻译：

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1 型糖尿病依赖于转录抑制因子 Bcl6 的 CD4 驱动表达


高亲和力胰岛自身抗体可预测小鼠和人类的 1 型糖尿病，并暗示生发中心 （GC） 与 1 型糖尿病的发病机制有关。1 型糖尿病个体的滤泡辅助性 T 细胞 （Tfh） 增加，外周血中 Tfh 样细胞的改变预测个体对阿巴西普的反应。Tfh 细胞支持 GC 反应，并依赖于转录抑制因子 BCL6 使其成熟。因此，我们假设 CD4 驱动的 Bcl6 缺失会破坏 GC 中重要的 T-B 淋巴细胞相互作用以预防 1 型糖尿病。为了检验这一假设，我们生成了 Bcl6fl/fl-CD4.Cre.NOD 小鼠，发现它们对糖尿病有完全保护。Bcl6fl/fl-CD4.Cre.NOD 小鼠胰腺中保留了胰岛素炎的严重程度和三级淋巴结构组织，相对于对照 Bcl6fl/fl，胰腺和引流淋巴结中的 CD4 + 、 CD8 + 和 B 细胞数量没有减少。NOD 小鼠。CD4 驱动的功能性 BCL6 缺失导致糖尿病前期晚期胰腺淋巴结和胰腺中的 GC B 细胞和 Tfh 细胞数量显着减少。Bcl6fl/fl-CD4.Cre.NOD 小鼠的自发性抗胰岛素自身抗体减弱。这些数据突出了 BCL6 作为 1 型糖尿病的新型治疗靶点。