Research ArticleMUCOSAL IMMUNOLOGY

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

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Science Immunology  13 Nov 2020:
Vol. 5, Issue 53, eabc6259
DOI: 10.1126/sciimmunol.abc6259

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IL-33 and roundworm clearance

Immune control of helminth infections is achieved via type 2 immune responses involving group 2 innate lymphoid cells (ILC2), with the cytokine interleukin-33 (IL-33) supporting the expansion and activation of ILC2. Hung et al. used a mouse model of Nippostrongylus brasiliensis infection to investigate the effects of selectively deleting the IL-33 gene in intestinal epithelial cells or CD11c+ dendritic cells (DCs). Epithelial cell IL-33 promoted clearance of infection by ILC2, but IL-33 from DCs instead impaired worm clearance by enhancing Treg function. IL-33 expression by DCs increased expression of the pore-forming protein perforin-2, which may provide a conduit on the plasma membrane for IL-33 to leave the cell. These findings provide new insights into the cellular mechanisms controlling extracellular release of IL-33.

Abstract

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.

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