Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
The Max McGee Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI.
J Immunol. 2023 Apr 1;210(7):935-946. doi: 10.4049/jimmunol.2200712.
IL-21 is essential for type 1 diabetes (T1D) development in the NOD mouse model. IL-21-expressing CD4 T cells are present in pancreatic islets where they contribute to T1D progression. However, little is known about their phenotype and differentiation states. To fill this gap, we generated, to our knowledge, a novel IL-21 reporter NOD strain to further characterize IL-21+ CD4 T cells in T1D. IL-21+ CD4 T cells accumulate in pancreatic islets and recognize β cell Ags. Single-cell RNA sequencing revealed that CD4 T effector cells in islets actively express IL-21 and they are highly diabetogenic despite expressing multiple inhibitory molecules, including PD-1 and LAG3. Islet IL-21+ CD4 T cells segregate into four phenotypically and transcriptionally distinct differentiation states, that is, less differentiated early effectors, T follicular helper (Tfh)-like cells, and two Th1 subsets. Trajectory analysis predicts that early effectors differentiate into both Tfh-like and terminal Th1 cells. We further demonstrated that intrinsic IL-27 signaling controls the differentiation of islet IL-21+ CD4 T cells, contributing to their helper function. Collectively, our study reveals the heterogeneity of islet-infiltrating IL-21+ CD4 T cells and indicates that both Tfh-like and Th1 subsets produce IL-21 throughout their differentiation process, highlighting the important sources of IL-21 in T1D pathogenesis.
IL-21 对于 NOD 小鼠模型中的 1 型糖尿病(T1D)的发展是必不可少的。IL-21 表达的 CD4 T 细胞存在于胰岛中,它们有助于 T1D 的进展。然而,人们对它们的表型和分化状态知之甚少。为了填补这一空白,我们生成了一种新型的 IL-21 报告 NOD 品系,以进一步研究 T1D 中 IL-21+ CD4 T 细胞。IL-21+ CD4 T 细胞在胰岛中积累,并识别β细胞抗原。单细胞 RNA 测序显示,胰岛中的 CD4 T 效应细胞积极表达 IL-21,尽管它们表达多种抑制分子,包括 PD-1 和 LAG3,但它们具有高度的致糖尿病性。胰岛 IL-21+ CD4 T 细胞分为四个表型和转录上不同的分化状态,即分化程度较低的早期效应物、滤泡辅助性 T 细胞(Tfh)样细胞和两个 Th1 亚群。轨迹分析预测,早期效应物分化为 Tfh 样细胞和终末 Th1 细胞。我们进一步证明,固有 IL-27 信号控制胰岛 IL-21+ CD4 T 细胞的分化,有助于其辅助功能。总之,我们的研究揭示了胰岛浸润的 IL-21+ CD4 T 细胞的异质性,并表明 Tfh 样和 Th1 亚群在其分化过程中都产生 IL-21,突出了 IL-21 在 T1D 发病机制中的重要来源。