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. [Display omitted] •Interleukin-33 (IL-33) promotes the expansion of stem-like CD8 T cells (CD8+SL)•IL-33 signals augment chromatin accessibility of CD8+SL in chronic viral infection•IL-33 prevents the loss of Tcf-1 expression by balancing type I interferon effects•IL-33 signaling to CD8+SL preserves these cells’ stemness and re-expansion capacity Stem-like Tcf-1-expressing CD8 T cells (CD8+SL) are key to immune defense in chronic infection and cancer, but the cytokine signals that promote CD8+SL cell expansion and stemness remain undefined. Marx et al. reveal that interleukin-33 assumes this role by balancing type I interferon signals and augmenting chromatin accessibility of CD8+SL.