The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8 T cells in chronic viral infection (ATAC-Seq)

T-cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these memory-like CD8 T cell (CD8ML) remain poorly defined. Studying CD8 T cell differentiation in mice with chronic viral infection we identify the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8ML as well as for virus control. IL-33 receptor- (ST2-) deficient CD8 T cells exhibit biased end-differentiation and premature loss of Tcf-1. Intriguingly, ST2-deficient CD8ML responses are restored by blockade of type I interferon signaling, suggesting that opposing IFN-I and IL-33 effects control CD8ML formation in chronic infection. IL-33 signals broadly augment chromatin accessibility in CD8ML and determine these cells’ re-expansion potential. Our study identifies the IL-33 – ST2 axis as an important CD8ML-promoting pathway in the context of chronic viral infection. ATAC-seq analysis of P14 WT Tcf7gpf+ cells and of P14 ST2-/- Tcf7gpf+ cells on day 4 after LCMV infection

表达T细胞因子1（T-cell factor 1, Tcf-1）的CD8阳性T细胞具备干细胞样自我更新能力，是机体对抗慢性病毒感染与癌症的免疫防御关键细胞群。然而，调控此类记忆样CD8阳性T细胞（memory-like CD8 T cell, CD8ML）形成与维持的信号机制仍未被充分阐明。本研究借助慢性病毒感染小鼠模型探究CD8 T细胞分化过程，鉴定出警报素白细胞介素-33（alarmin interleukin-33, IL-33）对CD8ML的扩增、干细胞样功能维持以及病毒控制均发挥关键调控作用。缺失IL-33受体（ST2）的CD8 T细胞呈现偏向终末分化的表型，并出现Tcf-1的过早丢失现象。有趣的是，阻断I型干扰素信号通路可恢复ST2缺陷型CD8ML的应答能力，这提示相互拮抗的I型干扰素（IFN-I）与IL-33信号共同调控慢性感染状态下CD8ML的形成。IL-33信号可广泛增强CD8ML的染色质可及性，并决定该细胞群的再扩增潜能。本研究证实IL-33-ST2信号轴是慢性病毒感染环境中促进CD8ML生成的重要通路。本数据集包含淋巴细胞脉络丛脑膜炎病毒（LCMV）感染后第4天，对P14野生型Tcf7gpf阳性细胞与P14 ST2基因敲除型Tcf7gpf阳性细胞开展的转座酶可及性测序（ATAC-seq）分析。