Cellular context of IL-33 expression dictates impact on anti-helminth immunity
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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Supplementary Material
Summary
Fig. S1. Validation of conditional KO lines, parasite infection models, and the effect of antibiotics on parasite clearance.
Fig. S2. Dysregulated Treg phenotype and enhanced worm clearance in Foxp3Cre Gata3fl/fl mice.
Fig. S3. Identification of IL-33-GFP–expressing myeloid cell types in spleen and lung.
Fig. S4. Characterization of costimulatory molecules and TLR ligand–induced cytokine production from DCs derived from CD11cCre versus CD11cCreIL-33fl/fl mice.
Fig. S5. Cytoplasmic IL-33–expressing cells in the vicinity of intestinal Foxp3+Treg and BMDC spontaneously secrete IL-33.
Fig. S6. DC-intrinsic IL-33 controls differential gene expression and surface expression of perforin-2 in CD103+ cDC.
Fig. S7. Generation of founder Mpeg1-deficient mice and DC–T cell culture controls.
Fig. S8. Proposed working model for an IL-33/perforin-2 axis.
Table S1. Ingenuity Pathway Analysis showing genes involved in cytokine transport pathways that are down-regulated in DCs lacking IL-33 as compared with IL-33–sufficient DCs (Excel spreadsheet).
Table S2. Ingenuity Pathway Analysis showing upstream transcriptional regulators down-regulated in DCs lacking IL-33 as compared with IL-33–sufficient DCs (Excel spreadsheet).
Table S3. Raw data file (Excel spreadsheet).
Resources
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Correction (8 January 2021): The red arrow in the ST2 vs. CD25 plot in Fig. 5N was removed.
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Science Immunology
Volume 5 | Issue 53
November 2020
November 2020
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Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 5 May 2020
Accepted: 28 September 2020
Acknowledgments
FACS and Amnis ImageStream studies were performed at the University of Pennsylvania Flow Cytometry core facility. N.V. is an undergraduate student at Drexel University, Philadelphia, PA. Funding: This work was supported by the Burroughs Wellcome Fund and the National Institutes of Health (R21-AI144572, U01-AI125940, and R01-GM083204 awarded to D.R.H.) Author contributions: L.-Y.H., Y.T., B.S., A.F., B.D., C.P., N.V., K.Z., B.L.B., C.L, D.R.R., and T.L.H.T. designed and conducted experiments. E.B., P.B., and N.A.C. provided critical reagents. T.K. and D.R.H. conceived the study and wrote the manuscript. K.H. designed and conducted experiments. M.A.K. provided critical reagents. Competing interests: P.B. is an employee of Sanofi-Genzyme and owns stock in Sanofi, a company with commercial interests in IL-33. The other authors declare that they have no competing interests. Data and materials availability: The Mpeg1-deficient mice generated as part of this study are available from the corresponding author upon request after completing a material transfer agreement. RNA-seq data were uploaded to the Gene Expression Omnibus repository. The bulk RNA-seq data accession number is GSE134581. The scRNA-seq accession number is GSE156285. All other data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.
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National Institutes of Health: R01-GM083204
National Institutes of Health: U01-AI125940
National Institutes of Health: R21-AI144572
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