최가람 (서울대학교)

한빛사논문

조회447

서울대학교

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Proc. Natl. Acad. Sci. USA, Jul 09 2024, 121 (28) | https://doi.org/10.1073/pnas.2319994121 NRF2 is a spatiotemporal metabolic hub essential for the polyfunctionality of Th2 cells

Garam Choi^a,1, Hye-Yeon Ju^b,1, Jahyun Bok^a,1, Jungseo Choi^a, Jae Woo Shin^c, Hansol Oh^d, Yeojin Jeon^a, Jiyeon Kim^a, Daehong Kim^a, Heesu Moon^a, Jeong-Eun Lee^a, Young-Sam Keum^e, You-Me Kim^f, Hye Young Kim^c, Sung Ho Park^d,2, Mi-Ryung Han^b,2, and Yeonseok Chung^a,2

^aLaboratory of Immune Regulation, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;

^bDivision of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea;

^cLaboratory of Mucosal Immunology in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;

^dLaboratory of Molecular Immunology, Department of Biological Science, Ulsan National Institute of Science & Technology, Ulsan 44919, Republic of Korea;

^eCollege of Pharmacy and Integrated Research, Institute for Drug Development, Dongguk University, Goyang 10326, Republic of Korea; and

^fGraduate School of Medical Scienceand Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea

¹G.C., H.- Y.J., and J.B. contributed equally to this work.

²To whom correspondence may be addressed.: Sung Ho Park, Mi-Ryung Han, Yeonseok Chung

Abstract

Upon encountering allergens, CD4 ⁺ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-04)
연구진국내 연구진
분야 생명과학 > 면역학

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