The curious case of IL-33 in homeostasis and infection

The importance of interleukin (IL)-33 in promoting effective antiviral immune responses is evident, yet the critical cellular sources of IL-33 in homeostasis and infection are largely unknown. In this issue of the European Journal of Immunology, Aparicio-Domingo et al. [Eur. J. Immunol. 2021. 51: 76-90] explore the main source of IL-33 expression in lymph nodes (LNs) and dissect its role in LN homeostasis and antiviral adaptive immune response. The authors reveal that fibroblastic reticular cells and lymphatic endothelial cells are both producing IL-33 in steady-state LNs. Remarkably, however, by using cell-type specific deletion approaches, the authors demonstrate that exclusively fibroblastic reticular cells, and not lymphatic endothelial cells, are the critical cellular source for promoting antiviral CD8⁺ T-cell responses upon infection. These findings provide an important insight into the role of specific LN stromal cell subsets as potent modulators of antiviral immunity.