Skin γδ T cell Inflammatory Responses Are Hardwired in the Thymus by Oxysterol Sensing Via GPR183 and Calibrated by Dietary Cholesterol

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2023 Feb 26

PMID 36842431

Authors

Michela Frascoli

Enxhi Ferraj

Bing Miu

Justin Malin

Nicholas A Spidale

Jennifer Cowan

Susannah C Shissler

Robert Brink

Ying Xu

Jason G Cyster

Avinash Bhandoola

Joonsoo Kang

Andrea Reboldi

Affiliations

Soon will be listed here.

Abstract

Dietary components and metabolites have a profound impact on immunity and inflammation. Here, we investigated how sensing of cholesterol metabolite oxysterols by γδ T cells impacts their tissue residency and function. We show that dermal IL-17-producing γδ T (Tγδ17) cells essential for skin-barrier homeostasis require oxysterols sensing through G protein receptor 183 (GPR183) for their development and inflammatory responses. Single-cell transcriptomics and murine reporter strains revealed that GPR183 on developing γδ thymocytes is needed for their maturation by sensing medullary thymic epithelial-cell-derived oxysterols. In the skin, basal keratinocytes expressing the oxysterol enzyme cholesterol 25-hydroxylase (CH25H) maintain dermal Tγδ17 cells. Diet-driven increases in oxysterols exacerbate Tγδ17-cell-mediated psoriatic inflammation, dependent on GPR183 on γδ T cells. Hence, cholesterol-derived oxysterols control spatially distinct but biologically linked processes of thymic education and peripheral function of dermal T cells, implicating diet as a focal parameter of dermal Tγδ17 cells.

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