The alarmin IL-33 promotes Tcf-1+ CD8+ T cells in chronic viral infections

Chronic CD8⁺ T cell responses to viral infections and cancer are maintained by a distinct subset of stem-like CD8⁺ T cells (CD8⁺SL) characterized by expression of the transcription factor TCF-1 and the inhibitory receptor PD-1. In contrast to terminally differentiated effector cells, CD8⁺SL maintain a high self-renewing capacity and robust expansion potential thus ensuring long-term T cell population maintenance under conditions of chronic antigen exposure. While recent studies have shown that CD8⁺SL are critical mediators of antitumoral T cell responses following immune checkpoint inhibition, the signals that control formation and maintenance of Tcf-1⁺ CD8⁺SL remained largely undefined.

A joint study by Daniel Pinschewer’s group at the University of Basel and Max Löhning`s group at the DRFZ and Charité – Universitätsmedizin Berlin, has now identified the alarmin IL-33 as a molecule essential for the expansion and stem-like functioning of CD8⁺SL in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). By signaling through its receptor ST2, IL-33 was shown to positively regulate the expression of Tcf7 (encoding TCF-1), thus counterbalancing the type-1 interferon-mediated loss of this stemness-promoting transcription factor. Further, the research team demonstrated that IL-33 signals received early during infection broadly augmented chromatin accessibility in CD8⁺SL thus imprinting an epigenetic signature that ensures high self-renewal capacity and warrants sustainable antiviral CD8+ T cell responses to chronic viral infection. The important role of IL-33-ST2 signaling for CD8⁺SL generation may help to understand the beneficial effects of IL-33 blockade in T cell-driven inflammatory diseases and provides a rationale for ongoing efforts to harness alarmin signaling in tumor immunotherapy.