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

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.