The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses

Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as “damage-associated molecular patterns” or “alarmins”, remains ill-defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8+ T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a MyD88-dependent, CTL-intrinsic fashion, determined polyfunctional effector cell differentiation and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses. 2 groups (wt vs. ST-/- P14 cells), 3 replicates per group.