Macrophage-derived oxysterols organize T helper 2 cells to suppress type 1 inflammation during pulmonary fungal infection.

Authors

Yufan Zheng, Hannah E Dobson, Makheni Jean Pierre, Lillian B LeBlanc, Chinaemerem U Onyishi, Dominic P Golec, Nathan Carrillo, Anshu Deewan, Claudia A Rivera, Eduard Ansaldo, Pamela L Schwartzberg, Eric V Dang

Published in

Science immunology. Volume 11. Issue 121. Pages eaee0990. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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_H2) 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_H2 cells into infectious lesions. This T_H2 cell positioning suppressed interferon-γ responsiveness in inflammatory Ly6C⁺ macrophages, promoting fungal persistence. Disruption of this axis via T_H2-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.

PMID:
42467744
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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