mTORC2 acts as a gatekeeper for mTORC1 deficiency-mediated impairments in ILC3 development

Ya-fei Deng1,2, Shu-ting Wu1, Hong-yan Peng1, Lei Tian3, Ya-na Li1, Yao Yang2, Meng Meng2, Lan-lan Huang1, Pei-wen Xiong1, Song-yang Li1, Qing-lan Yang1, Li-li Wang1, Xiao-yao Li4, Li-ping Li1, Xiu-lan Lu1, Xiao-hui Li2, Yan-ling Wei5, Zheng-hui Xiao1, Jian-hua Yu3, You-cai Deng2
1 Pediatrics Research Institute of Hunan Province and Hunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha 410007, China
2 Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing 400038, China
3 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA
4 Department of Clinical Pharmacy, Weifang Traditional Chinese Hospital, Weifang 261041, China
5 Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University, Chongqing 400042, China
Correspondence to: Yan-ling Wei:, Zheng-hui Xiao:, Jian-hua Yu:, You-cai Deng:,
DOI: 10.1038/s41401-023-01120-8
Received: 7 February 2023
Accepted: 31 May 2023
Advance online: 5 July 2023


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.

Keywords: Group 3 innate lymphoid cells; mTORC1; mTORC2; NFIL3; single-cell RNA sequencing

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