The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses

Sound the Alarm When small protein fragments or nucleic acids derived from an invading pathogen are detected by pattern recognition receptors on immune cells, the innate immune response is triggered. This event activates cells of the adaptive immune system, and together, both responses clear the infection. Infections also induce the release of “danger-associated molecular patterns,” or alarmins, from the host as a result of tissue damage. Whether these are also important for the ensuing immune response is less clear. Bonilla et al. (p. 984, published online 2 February) report that the alarmin, interleukin-33, is required for optimal cytotoxic CD8+ T cells responses and antiviral immunity in mice. In virus-infected mice deficient in IL-33 or its receptor, IL-33 is essential for signaling CD8+ T cells to expand, produce multiple cytokines and acquire cytotoxic capabilities. These results showed that endogenous material, independently of pathogen-derived molecules, are also required for antiviral immunity. A danger signal released from dying cells is required for antiviral immunity in mice. 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 CTL-intrinsic fashion, determined plurifunctional 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.