PMID- 31167146 OWN - NLM STAT- MEDLINE DCOM- 20200731 LR - 20211204 IS - 2211-1247 (Electronic) VI - 27 IP - 10 DP - 2019 Jun 4 TI - Differential Roles of the mTOR-STAT3 Signaling in Dermal gammadelta T Cell Effector Function in Skin Inflammation. PG - 3034-3048.e5 LID - S2211-1247(19)30630-8 [pii] LID - 10.1016/j.celrep.2019.05.019 [doi] AB - Dermal gammadeltaT cells play critical roles in skin homeostasis and inflammation. However, the underlying molecular mechanisms by which these cells are activated have not been fully understood. Here, we show that the mechanistic or mammalian target of rapamycin (mTOR) and STAT3 pathways are activated in dermal gammadeltaT cells in response to innate stimuli such as interleukin-1beta (IL-1beta) and IL-23. Although both mTOR complex 1 (mTORC1) and mTORC2 are essential for dermal gammadeltaT cell proliferation, mTORC2 deficiency leads to decreased dermal gammadeltaT17 cells. It appears that mitochondria-mediated oxidative phosphorylation is critical in this process. Notably, although the STAT3 pathway is critical for dermal Vgamma4T17 effector function, it is not required for Vgamma6T17 cells. Transcription factor IRF-4 activation promotes dermal gammadeltaT cell IL-17 production by linking IL-1beta and IL-23 signaling. The absence of mTORC2 in dermal gammadeltaT cells, but not STAT3, ameliorates skin inflammation. Taken together, our results demonstrate that the mTOR-STAT3 signaling differentially regulates dermal gammadeltaT cell effector function in skin inflammation. CI - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Cai, Yihua AU - Cai Y AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Xue, Feng AU - Xue F AD - Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China. FAU - Qin, Hui AU - Qin H AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China. FAU - Chen, Xu AU - Chen X AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Laboratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China. FAU - Liu, Na AU - Liu N AD - Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China. FAU - Fleming, Chris AU - Fleming C AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Hu, Xiaoling AU - Hu X AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Zhang, Huang-Ge AU - Zhang HG AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Chen, Fuxiang AU - Chen F AD - Department of Laboratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China. FAU - Zheng, Jie AU - Zheng J AD - Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China. FAU - Yan, Jun AU - Yan J AD - Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. Electronic address: jun.yan@louisville.edu. LA - eng GR - R01 AI128818/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Interferon Regulatory Factors) RN - 0 (Interleukin-17) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - 0 (STAT3 Transcription Factor) RN - 0 (interferon regulatory factor-4) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Cell Proliferation/drug effects MH - Disease Models, Animal MH - Humans MH - Interferon Regulatory Factors/antagonists & inhibitors/genetics/metabolism MH - Interleukin-17/metabolism MH - Intraepithelial Lymphocytes/cytology/*metabolism MH - Mechanistic Target of Rapamycin Complex 2/deficiency/genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mitochondria/metabolism MH - Psoriasis/diagnosis/pathology MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Reactive Oxygen Species/metabolism MH - STAT3 Transcription Factor/*metabolism MH - Signal Transduction MH - Skin/metabolism/pathology MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC6617524 MID - NIHMS1531460 OTO - NOTNLM OT - IL-1 signaling OT - IL-17 OT - IL-23 signaling OT - STAT3 OT - Vgamma4 OT - Vgamma6 OT - gammadelta T cells OT - mTOR OT - psoriasis OT - skin inflammation COIS- DECLARATION OF INTERESTS The authors declare no competing interests. EDAT- 2019/06/06 06:00 MHDA- 2020/08/01 06:00 PMCR- 2019/07/10 CRDT- 2019/06/06 06:00 PHST- 2018/11/20 00:00 [received] PHST- 2019/04/04 00:00 [revised] PHST- 2019/05/02 00:00 [accepted] PHST- 2019/06/06 06:00 [entrez] PHST- 2019/06/06 06:00 [pubmed] PHST- 2020/08/01 06:00 [medline] PHST- 2019/07/10 00:00 [pmc-release] AID - S2211-1247(19)30630-8 [pii] AID - 10.1016/j.celrep.2019.05.019 [doi] PST - ppublish SO - Cell Rep. 2019 Jun 4;27(10):3034-3048.e5. doi: 10.1016/j.celrep.2019.05.019.