Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin

H. Takahashi, H. Nomura, H. Iriki, A. Kubo, K. Isami, Y. Mikami, M. Mukai, T. Sasaki, J. Yamagami, J. Kudoh, H. Ito, A. Kamata, Y. Kurebayashi, H. Yoshida, A. Yoshimura, H. W. Sun, M. Suematsu, J. J. O’Shea, Y. Kanno, M. Amagai

Research output: Contribution to journalArticlepeer-review

Abstract

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor–β (TGF-β), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-β signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27–treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

Original languageEnglish
Article numbereabb6444
JournalScience Immunology
Volume6
Issue number64
DOIs
Publication statusPublished - 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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