McNitt Dudley H, Williams Jonathan M, Santitoro Joseph G, Kim Jacob, Thomas James W, Bonami Rachel H
Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.
Diabetes. 2025 Jun 1;74(6):921-932. doi: 10.2337/db23-0709.
High-affinity islet autoantibodies predict type 1 diabetes in mice and humans and implicate germinal centers (GCs) in disease pathogenesis. T follicular helper (Tfh) cells are increased in individuals with type 1 diabetes 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. Therefore, we hypothesized that CD4-driven deletion of Bcl6 would disrupt essential T- and B-cell 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.
Germinal center B cells and CD4+ T follicular helper cells are implicated in the pathogenesis of type 1 diabetes and depend upon the transcriptional repressor BCL6 for their maturation. This study tests the dependence of type 1 diabetes development on BCL6 expression in CD4+ cells. Data presented here show that CD4-driven loss of Bcl6 blocks germinal center formation, spontaneous insulin autoantibody production, and type 1 diabetes in nonobese diabetic mice, despite normal tertiary lymphoid structure formation in pancreatic islets. This study highlights BCL6 as a potential immunomodulatory target in type 1 diabetes.
高亲和力胰岛自身抗体可预测小鼠和人类的1型糖尿病，并提示生发中心（GCs）参与疾病发病机制。1型糖尿病患者的T滤泡辅助（Tfh）细胞增多，外周血中Tfh样细胞的改变可预测个体对阿巴西普的反应。Tfh细胞支持GC反应，其成熟依赖于转录抑制因子BCL6。因此，我们假设CD4驱动的Bcl6缺失会破坏GC中关键的T细胞和B细胞相互作用，从而预防1型糖尿病。为了验证这一假设，我们构建了Bcl6fl/fl-CD4.Cre.NOD小鼠，发现它们完全受到糖尿病的保护。与对照Bcl6fl/fl.NOD小鼠相比，Bcl6fl/fl-CD4.Cre.NOD小鼠胰腺中的胰岛炎严重程度和三级淋巴结构组织得以保留，其胰腺和引流淋巴结中的CD4 +、CD8 +和B细胞数量没有减少。在糖尿病前期晚期，CD4驱动的功能性BCL6缺失导致胰腺淋巴结和胰腺中GC B细胞和Tfh细胞数量显著减少。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型糖尿病的一个新的治疗靶点。
生发中心B细胞和CD4 + T滤泡辅助细胞参与1型糖尿病的发病机制，其成熟依赖于转录抑制因子BCL6。本研究测试了1型糖尿病发展对CD4 +细胞中BCL6表达的依赖性。这里呈现的数据表明，尽管胰岛中三级淋巴结构形成正常，但CD4驱动的Bcl6缺失会阻断非肥胖糖尿病小鼠的生发中心形成、自发性胰岛素自身抗体产生和1型糖尿病。本研究突出了BCL6作为1型糖尿病潜在免疫调节靶点的作用。
