PMID- 34132158
OWN - NLM
STAT- MEDLINE
DCOM- 20220706
LR  - 20220718
IS  - 1532-4311 (Electronic)
IS  - 0882-0139 (Linking)
VI  - 51
IP  - 5
DP  - 2022 Jul
TI  - Activation of Gonadotropin-releasing Hormone Receptor Impedes the 
      Immunosuppressive Activity of Decidual Regulatory T Cells via Deactivating the 
      Mechanistic Target of Rapamycin Signaling.
PG  - 1330-1346
LID - 10.1080/08820139.2021.1937208 [doi]
AB  - Understanding maternal immune tolerance is crucial for the development of 
      therapeutics for immunological pregnancy complications. Decidual regulatory T 
      cells (Tregs) play a pivotal role in the maintenance of maternal immune 
      tolerance. Using a murine allogeneic pregnancy model in the current study, we 
      identified the up-regulation of gonadotropin-releasing hormone receptor (GnRHR) 
      in decidual T cell subsets including CD4(+) conventional T cells, CD8(+) T cells, 
      and CD4(+)Foxp3(+) Tregs. Using a lentivirus-mediated GnRHR overexpression system 
      and a GnRHR agonist, we found that GnRHR activation decreased the expression of 
      Treg functional molecules such as IL10 (IL-10), IL-35 subunit EBI3 (Ebi3), IL2RA 
      (CD25), TNFRSF18 (GITR), ICOS, and Treg master regulator FOXP3. The functional 
      analysis indicated that GnRHR activation impairs the ability of Tregs to inhibit 
      conventional T cell proliferation. We also revealed that GnRHR activation 
      suppressed the mechanistic target of rapamycin (mTOR) signaling in 
      GnRHR-overexpressing splenic Tregs (Wild type C57BL/6 J background) and decidual 
      Tregs. MHY1485, a potent mTOR activator, effectively abolished the effect of the 
      GnRHR agonist and promoted the immunosuppressive capability of Tregs. 
      Furthermore, in an adoptive transfer model, Treg-specific GnRHR knockdown 
      increased Foxp3 expression in decidual Tregs while decreasing the production of 
      IFN-gamma and IL-17 in decidual effector CD4(+) T cells and reducing the production 
      of IFN-gamma in decidual effector CD8(+) T cells. Taken together, the present study 
      unveils a novel mechanism by which the immunosuppressive function of decidual 
      Tregs is modulated, and deepens our understanding of maternal immune tolerance.
FAU - Wang, Xuejin
AU  - Wang X
AD  - Department of Reproductive Medicine, Shenzhen Zhongshan Urology Hospital, 
      Shenzhen, Guangdong, People's Republic of China.
FAU - Zhong, Liangying
AU  - Zhong L
AD  - Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, People's Republic of China.
FAU - Liu, Qiaodan
AU  - Liu Q
AD  - Department of Head and Neck Oncology, The Cancer Center of the Fifth Affiliated 
      Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of 
      China.
FAU - Cai, Peiya
AU  - Cai P
AD  - Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Fujian 
      Medical University, Quanzhou, Fujian, People's Republic of China.
FAU - Zhang, Peiru
AU  - Zhang P
AD  - Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Fujian 
      Medical University, Quanzhou, Fujian, People's Republic of China.
FAU - Lu, Zhilan
AU  - Lu Z
AD  - Department of Preventive Medicine, School of Public Health, Fujian Medical 
      University, Fuzhou, Fujian Province, People's Republic of China.
FAU - Li, Xiaoqin
AU  - Li X
AD  - Department of Preventive Medicine, School of Public Health, Fujian Medical 
      University, Fuzhou, Fujian Province, People's Republic of China.
FAU - Liu, Jin
AU  - Liu J
AUID- ORCID: 0000-0002-0000-8649
AD  - Department of Preventive Medicine, School of Public Health, Fujian Medical 
      University, Fuzhou, Fujian Province, People's Republic of China.
LA  - eng
PT  - Journal Article
DEP - 20210616
PL  - England
TA  - Immunol Invest
JT  - Immunological investigations
JID - 8504629
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Receptors, LHRH)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Female
MH  - Forkhead Transcription Factors/immunology
MH  - *Immune Tolerance/immunology
MH  - Mice
MH  - *Pregnancy/immunology
MH  - *Receptors, LHRH/immunology
MH  - *T-Lymphocytes, Regulatory/immunology
MH  - *TOR Serine-Threonine Kinases/immunology
OTO - NOTNLM
OT  - Decidual regulatory T cells
OT  - gonadotropin-releasing hormone receptor
OT  - maternal immune tolerance
EDAT- 2021/06/17 06:00
MHDA- 2022/07/07 06:00
CRDT- 2021/06/16 08:51
PHST- 2021/06/17 06:00 [pubmed]
PHST- 2022/07/07 06:00 [medline]
PHST- 2021/06/16 08:51 [entrez]
AID - 10.1080/08820139.2021.1937208 [doi]
PST - ppublish
SO  - Immunol Invest. 2022 Jul;51(5):1330-1346. doi: 10.1080/08820139.2021.1937208. 
      Epub 2021 Jun 16.