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 stem-like CD8⁺ T cells (CD8⁺SL) remain poorly defined.

Studying CD8⁺ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8⁺SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8⁺ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8⁺SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8⁺SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8⁺SL and determined these cells’ re-expansion potential.

Our study identifies the IL-33-ST2 axis as an important CD8⁺SL-promoting pathway in the context of chronic viral infection.

^{表达 CD8 +} T 细胞的 T 细胞因子 1 (Tcf-1)表现出干细胞样自我更新能力，使它们成为针对慢性病毒感染和癌症的免疫防御的关键。^{然而，促进这些干细胞样 CD8 +} T 细胞 (CD8 ⁺ SL)形成和维持的信号仍不清楚。

通过研究慢性病毒感染小鼠的 CD8 ^{+ T 细胞分化，我们确定了 alarmin interleukin-33 (IL-33) 是 CD8 +} SL的扩增和干细胞样功能以及病毒控制的关键。IL-33 受体 (ST2) 缺陷型 CD8 ⁺ T 细胞表现出偏向的末端分化和 Tcf-1 过早丢失。ST2 缺陷型 CD8 ⁺ SL 反应通过阻断 I 型干扰素信号转导得到恢复，表明 IL-33 平衡 IFN-I 效应以控制慢性感染中 CD8 ⁺ SL 的形成。IL-33 信号广泛增强了 CD8 ⁺ SL 中的染色质可及性，并确定了这些细胞的再扩增潜力。

我们的研究将 IL-33-ST2 轴确定为慢性病毒感染背景下重要的 CD8 ^{+ SL 促进途径。}