PMID- 37407703 OWN - NLM STAT- MEDLINE DCOM- 20231102 LR - 20231103 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 44 IP - 11 DP - 2023 Nov TI - mTORC2 acts as a gatekeeper for mTORC1 deficiency-mediated impairments in ILC3 development. PG - 2243-2252 LID - 10.1038/s41401-023-01120-8 [doi] AB - Group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function. Recent studies have investigated the role of the mammalian target of rapamycin complex (mTOR) in ILC3s, whereas the mTORC1-related mechanisms and crosstalk between mTORC1 and mTORC2 involved in regulating ILC3 homeostasis remain unknown. In this study, we found that mTORC1 but not mTORC2 was critical in ILC3 development, IL-22 production, and ILC3-mediated intestinal homeostasis. Single-cell RNA sequencing revealed that mTORC1 deficiency led to disruption of ILC3 heterogeneity, showing an increase in differentiation into ILC1-like phenotypes. Mechanistically, mTORC1 deficiency decreased the expression of NFIL3, which is a critical transcription factor responsible for ILC3 development. The activities of both mTORC1 and mTORC2 were increased in wild-type ILC3s after activation by IL-23, whereas inhibition of mTORC1 by Raptor deletion or rapamycin treatment resulted in increased mTORC2 activity. Previous studies have demonstrated that S6K, the main downstream target of mTORC1, can directly phosphorylate Rictor to dampen mTORC2 activity. Our data found that inhibition of mTORC1 activity by rapamycin reduced Rictor phosphorylation in ILC3s. Reversing the increased mTORC2 activity via heterozygous or homozygous knockout of Rictor in Raptor-deleted ILC3s resulted in severe ILC3 loss and complete susceptibility to intestinal infection in mice with mTORC1 deficiency (100% mortality). Thus, mTORC1 acts as a rheostat of ILC3 heterogeneity, and mTORC2 protects ILC3s from severe loss of cells and immune activity against intestinal infection when mTORC1 activity is diminished. CI - (c) 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. FAU - Deng, Ya-Fei AU - Deng YF AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. AD - Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing, 400038, China. FAU - Wu, Shu-Ting AU - Wu ST AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Peng, Hong-Yan AU - Peng HY AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Tian, Lei AU - Tian L AD - Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. FAU - Li, Ya-Na AU - Li YN AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Yang, Yao AU - Yang Y AD - Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing, 400038, China. FAU - Meng, Meng AU - Meng M AD - Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing, 400038, China. FAU - Huang, Lan-Lan AU - Huang LL AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Xiong, Pei-Wen AU - Xiong PW AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Li, Song-Yang AU - Li SY AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Yang, Qing-Lan AU - Yang QL AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Wang, Li-Li AU - Wang LL AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Li, Xiao-Yao AU - Li XY AD - Department of Clinical Pharmacy, Weifang Traditional Chinese Hospital, Weifang, 261041, China. FAU - Li, Li-Ping AU - Li LP AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Lu, Xiu-Lan AU - Lu XL AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. FAU - Li, Xiao-Hui AU - Li XH AD - Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing, 400038, China. FAU - Wei, Yan-Ling AU - Wei YL AD - Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University, Chongqing, 400042, China. lingzi016@126.com. FAU - Xiao, Zheng-Hui AU - Xiao ZH AD - Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, 410007, China. xiaozhenghui888@163.com. FAU - Yu, Jian-Hua AU - Yu JH AD - Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. Jiayu@coh.org. FAU - Deng, You-Cai AU - Deng YC AD - Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing, 400038, China. youcai.deng@tmmu.edu.cn. LA - eng PT - Journal Article DEP - 20230705 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - 0 (Rapamycin-Insensitive Companion of mTOR Protein) RN - 0 (Regulatory-Associated Protein of mTOR) RN - 0 (Transcription Factors) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Mice MH - Animals MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Mechanistic Target of Rapamycin Complex 2/metabolism MH - *Immunity, Innate MH - Rapamycin-Insensitive Companion of mTOR Protein/metabolism MH - *Lymphocytes MH - Regulatory-Associated Protein of mTOR/genetics MH - Transcription Factors/metabolism MH - Sirolimus/pharmacology MH - Mammals/metabolism PMC - PMC10618277 OTO - NOTNLM OT - Group 3 innate lymphoid cells OT - NFIL3 OT - mTORC1 OT - mTORC2 OT - single-cell RNA sequencing COIS- The authors declare no competing interests. EDAT- 2023/07/06 01:08 MHDA- 2023/11/02 12:42 PMCR- 2024/11/01 CRDT- 2023/07/05 23:28 PHST- 2023/02/07 00:00 [received] PHST- 2023/05/31 00:00 [accepted] PHST- 2024/11/01 00:00 [pmc-release] PHST- 2023/11/02 12:42 [medline] PHST- 2023/07/06 01:08 [pubmed] PHST- 2023/07/05 23:28 [entrez] AID - 10.1038/s41401-023-01120-8 [pii] AID - 1120 [pii] AID - 10.1038/s41401-023-01120-8 [doi] PST - ppublish SO - Acta Pharmacol Sin. 2023 Nov;44(11):2243-2252. doi: 10.1038/s41401-023-01120-8. Epub 2023 Jul 5.