Cellular context of IL-33 expression dictates impact on anti-helminth immunity

Li Yin Hung, Yukinori Tanaka, Karl Herbine, Christopher Pastore, Brenal Singh, Annabel Ferguson, Nisha Vora, Bonnie Douglas, Kelly Zullo, Edward M. Behrens, Tiffany Li Hui Tan, Michael A. Kohanski, Paul Bryce, Cailu Lin, Taku Kambayashi, Danielle R. Reed, Breann L. Brown, Noam A. Cohen, De'Broski R. Herbert

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Interleukin-33 (IL-33) is a pleiotropic cytokine that can promote type 2 inflammation but also drives immunoregulation through Foxp3+Treg expansion. How IL-33 is exported from cells to serve this dual role in immunosuppression and inflammation remains unclear. Here, we demonstrate that the biological consequences of IL-33 activity are dictated by its cellular source. Whereas IL-33 derived from epithelial cells stimulates group 2 innate lymphoid cell (ILC2)-driven type 2 immunity and parasite clearance, we report that IL-33 derived from myeloid antigen-presenting cells (APCs) suppresses host-protective inflammatory responses. Conditional deletion of IL-33 in CD11c-expressing cells resulted in lowered numbers of intestinal Foxp3+Treg cells that express the transcription factor GATA3 and the IL-33 receptor ST2, causing elevated IL-5 and IL-13 production and accelerated anti-helminth immunity. We demonstrate that cell-intrinsic IL-33 promoted mouse dendritic cells (DCs) to express the pore-forming protein perforin-2, which may function as a conduit on the plasma membrane facilitating IL-33 export. Lack of perforin-2 in DCs blocked the proliferative expansion of the ST2+Foxp3+Treg subset. We propose that perforin-2 can provide a plasma membrane conduit in DCs that promotes the export of IL-33, contributing to mucosal immunoregulation under steady-state and infectious conditions.

Original languageEnglish
Article numbereabc6259
JournalScience immunology
Issue number53
Publication statusPublished - 2020 Nov


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