Treg deficiency-mediated TH1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells

被引:63
作者
Jiao, Xue [1 ,2 ,3 ,4 ]
Zhang, Xiruo [1 ,3 ,4 ]
Li, Nianyu [1 ,3 ,4 ]
Zhang, Dunfang [2 ]
Zhao, Shidou [1 ,3 ,4 ]
Dang, Yujie [1 ,3 ,4 ]
Zanvit, Peter [2 ]
Jin, Wenwen [2 ]
Chen, Zi-Jiang [1 ,3 ,4 ,5 ,6 ]
Chen, Wanjun [2 ]
Qin, Yingying [1 ,3 ,4 ]
机构
[1] Shandong Univ, Cheeloo Coll Med, Ctr Reprod Med, 157 Jingliu Rd, Jinan 250021, Shandong, Peoples R China
[2] NIDCR, Mucosal Immunol Sect, NIH, 30 Convent Dr, Bethesda, MD 20892 USA
[3] Shandong Univ, Natl Res Ctr Assisted Reprod Technol & Reprod Gen, Jinan, Shandong, Peoples R China
[4] Shandong Univ, Minist Educ, Key Lab Reprod Endocrinol, Jinan, Shandong, Peoples R China
[5] Shanghai Key Lab Assisted Reprod & Reprod Genet, Shanghai, Peoples R China
[6] Shanghai Jiao Tong Univ, Ctr Reprod Med, Ren Ji Hosp, Sch Med, Shanghai, Peoples R China
来源
CLINICAL AND TRANSLATIONAL MEDICINE | 2021年 / 11卷 / 06期
基金
美国国家卫生研究院; 中国国家自然科学基金;
关键词
apoptosis; granulosa cells; POI; steroidogenesis; T(H)1; T-reg cells; TRANSCRIPTION FACTOR; ESTROGEN; DIFFERENTIATION; MECHANISMS; EXPRESSION; INDUCTION; DISEASE; WOMEN; GAMMA; MICE;
D O I
10.1002/ctm2.448
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (T(H)1) responses and regulatory T (T-reg) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of T(H)1:T-reg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of T(H)1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by T-reg cells. Importantly, interferon (IFN) -gamma and tumor necrosis factor (TNF) -alpha cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized T-reg cell deficiency-mediated T(H)1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.
引用
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页数:20
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