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Proc. Natl. Acad. Sci. USA, Jun 11 2024, 121 (24) | https://doi.org/10.1073/pnas.2322009121 ETV5 promotes lupus pathogenesis and follicular helper T cell differentiation by inducing osteopontin expression

Jiho Park^a, Jongeun Lee^a, Yunjung Hur^a, Chan-Johng Kim^a, Han Bit Kim^a, Dahun Um^a, Da Som Kim^b, June-Yong Lee^c, Sungjun Park^d, Youngjae Park^e, Tae-Kyung Kim^a, Sin-Hyeog Im^a,f, Sung Won Kim^g, Seung-Ki Kwok^e, and Yoontae Lee^a,f,1

^aDepartment of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea;

^bThe Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;

^cDepartment of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;

^dDepartment of Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;

^eDivision of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;

^fInstitute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, Republic of Korea; and

^gDepartment of Otolaryngology- Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea

¹To whom correspondence may be addressed. : Yoontae Lee

Abstract

Follicular helper T (T _FH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes T _FH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated T _FH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes T _FH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances T _FH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4 ⁺ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes T _FH cell differentiation.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-10)
연구진국내 연구진
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