Macrophage-derived oxysterols organize T helper 2 cells to suppress type 1 inflammation during pulmonary fungal infection
Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear. Here, we identify a cholesterol-derived chemotactic axis that spatially organizes T helper 2 (T H 2) cells during fungal-induced pulmonary type 2 inflammation. Inflammation-expanded macrophages expressing cholesterol-25-hydroxylase (CH25H) produced 25-hydroxycholesterol, which was converted into the oxysterol 7α,25-dihydroxycholesterol to attract GPR183-expressing T H 2 cells into infectious lesions. This T H 2 cell positioning suppressed interferon-γ responsiveness in inflammatory Ly6C + macrophages, promoting fungal persistence. Disruption of this axis via T H 2-specific GPR183 deletion restored type 1 macrophage activation and enhanced fungal clearance. Our findings reveal a macrophage-driven, metabolite-based mechanism of immunosuppressive cell positioning in inflamed lung tissue.
Authors
- Chinaemerem U. Onyishi (ORCID: https://orcid.org/0000-0001-8292-9873)
- Dominic P. Golec (ORCID: https://orcid.org/0000-0002-2741-3302)
- Eric V. Dang (ORCID: https://orcid.org/0000-0002-2389-6167)
- Yufan Zheng (ORCID: https://orcid.org/0000-0002-4827-6191)
- Nathan Carrillo (ORCID: https://orcid.org/0000-0003-4216-7258)
- Hannah E. Dobson (ORCID: https://orcid.org/0000-0003-1246-880X)
- Taylor K. Farley (ORCID: https://orcid.org/0000-0002-9926-1475)
- Anshu Deewan (ORCID: https://orcid.org/0000-0002-0288-8926)
- Makheni Jean Pierre
- Pamela L. Schwartzberg (ORCID: https://orcid.org/0000-0001-6318-9187)
- Eduard Ansaldo (ORCID: https://orcid.org/0000-0002-7128-3373)
- Lillian B. LeBlanc (ORCID: https://orcid.org/0009-0004-7496-9073)
Institutions
- University of Pittsburgh (US)
- Georgetown University (US)
- National Institute of Allergy and Infectious Diseases (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1126/sciimmunol.aee0990
- Primary Topic
- Cholesterol and Lipid Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases