Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, 53213, USA.
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Nat Commun. 2018 Nov 28;9(1):5037. doi: 10.1038/s41467-018-07492-4.
During chronic viral infection, the inflammatory function of CD4 T-cells becomes gradually attenuated. Concurrently, Th1 cells progressively acquire the capacity to secrete the cytokine IL-10, a potent suppressor of antiviral T cell responses. To determine the transcriptional changes that underlie this adaption process, we applied a single-cell RNA-sequencing approach and assessed the heterogeneity of IL-10-expressing CD4 T-cells during chronic infection. Here we show an IL-10-producing population with a robust Tfh-signature. Using IL-10 and IL-21 double-reporter mice, we further demonstrate that IL-10IL-21co-producing Tfh cells arise predominantly during chronic but not acute LCMV infection. Importantly, depletion of IL-10IL-21co-producing CD4 T-cells or deletion of Il10 specifically in Tfh cells results in impaired humoral immunity and viral control. Mechanistically, B cell-intrinsic IL-10 signaling is required for sustaining germinal center reactions. Thus, our findings elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection.
在慢性病毒感染期间，CD4 T 细胞的炎症功能逐渐减弱。同时，Th1 细胞逐渐获得分泌细胞因子 IL-10 的能力，IL-10 是抗病毒 T 细胞反应的一种有效抑制剂。为了确定这种适应过程的转录变化基础，我们应用单细胞 RNA 测序方法评估了慢性感染期间表达 IL-10 的 CD4 T 细胞的异质性。在这里，我们展示了具有强大 Tfh 特征的产生 IL-10 的群体。使用 IL-10 和 IL-21 双报告小鼠，我们进一步证明 IL-10IL-21 共产生 Tfh 细胞主要在慢性而非急性 LCMV 感染期间产生。重要的是，耗尽 IL-10IL-21 共产生的 CD4 T 细胞或特异性缺失 Tfh 细胞中的 Il10 会导致体液免疫受损和病毒控制能力下降。从机制上讲，B 细胞内源性 IL-10 信号对于维持生发中心反应是必需的。因此，我们的研究结果阐明了 Tfh 细胞来源的 IL-10 在促进持续性病毒感染期间体液免疫中的关键作用。
