PMID- 30911060 OWN - NLM STAT- MEDLINE DCOM- 20200717 LR - 20211204 IS - 1748-7838 (Electronic) IS - 1001-0602 (Print) IS - 1001-0602 (Linking) VI - 29 IP - 5 DP - 2019 May TI - LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity. PG - 391-405 LID - 10.1038/s41422-019-0157-4 [doi] AB - Dendritic cells (DCs) play a pivotal role in priming adaptive immunity. However, the involvement of DCs in controlling excessive and deleterious T cell responses remains poorly defined. Moreover, the metabolic dependence and regulation of DC function are unclear. Here we show that LKB1 signaling in DCs functions as a brake to restrain excessive tumor-promoting regulatory T cell (Treg) and Th17 cell responses, thereby promoting protective anti-tumor immunity and maintaining proper immune homeostasis. LKB1 deficiency results in dysregulated metabolism and mTOR activation of DCs. Loss of LKB1 also leads to aberrant DC maturation and production of cytokines and immunoregulatory molecules. Blocking mTOR signaling in LKB1-deficient DCs partially rectifies the abnormal phenotypes of DC activation and Treg expansion, whereas uncontrolled Th17 responses depend upon IL-6-STAT3 signaling. By coordinating metabolic and immune quiescence of DCs, LKB1 acts as a crucial signaling hub in DCs to enforce protective anti-tumor immunity and normal immune homeostasis. FAU - Wang, Yanyan AU - Wang Y AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Du, Xingrong AU - Du X AUID- ORCID: 0000-0001-6427-9600 AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Wei, Jun AU - Wei J AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Long, Lingyun AU - Long L AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Tan, Haiyan AU - Tan H AD - Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. AD - Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Guy, Cliff AU - Guy C AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Dhungana, Yogesh AU - Dhungana Y AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Qian, Chenxi AU - Qian C AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. AD - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Neale, Geoffrey AU - Neale G AD - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Fu, Yang-Xin AU - Fu YX AUID- ORCID: 0000-0002-4809-825X AD - Department of Pathology, University of Texas (UT) Southwestern Medical Center, Dallas, TX, 75390, USA. FAU - Yu, Jiyang AU - Yu J AD - Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Peng, Junmin AU - Peng J AD - Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. AD - Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. FAU - Chi, Hongbo AU - Chi H AUID- ORCID: 0000-0002-9997-2496 AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. hongbo.chi@stjude.org. LA - eng GR - R01 AI131703/AI/NIAID NIH HHS/United States GR - R01 AG053987/AG/NIA NIH HHS/United States GR - P30 CA021765/CA/NCI NIH HHS/United States GR - R01 CA176624/CA/NCI NIH HHS/United States GR - R01 CA221290/CA/NCI NIH HHS/United States GR - R01 NS064599/NS/NINDS NIH HHS/United States GR - R37 AI105887/AI/NIAID NIH HHS/United States GR - R01 AI140761/AI/NIAID NIH HHS/United States GR - R01 AI105887/AI/NIAID NIH HHS/United States GR - R01 GM134382/GM/NIGMS NIH HHS/United States GR - R01 AI101407/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190325 PL - England TA - Cell Res JT - Cell research JID - 9425763 RN - 0 (Interleukin-17) RN - 0 (Interleukin-6) RN - 0 (STAT3 Transcription Factor) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Stk11 protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM CIN - Cell Res. 2019 Jun;29(6):429-431. PMID: 31024168 MH - AMP-Activated Protein Kinases MH - Animals MH - Cell Differentiation MH - Cell Line, Tumor MH - Dendritic Cells/cytology/*metabolism MH - Interferon-gamma/metabolism MH - Interleukin-17/metabolism MH - Interleukin-6/metabolism MH - Lymphocyte Activation MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neoplasms/immunology/pathology MH - Protein Serine-Threonine Kinases/deficiency/genetics/*metabolism MH - STAT3 Transcription Factor/metabolism MH - Signal Transduction MH - T-Lymphocytes, Regulatory/cytology/immunology/metabolism MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Th17 Cells/cytology/metabolism MH - Thymus Gland/metabolism PMC - PMC6796952 COIS- The authors declare that they have no conflict of interest. EDAT- 2019/03/27 06:00 MHDA- 2020/07/18 06:00 PMCR- 2020/05/01 CRDT- 2019/03/27 06:00 PHST- 2018/11/08 00:00 [received] PHST- 2019/03/03 00:00 [accepted] PHST- 2019/03/27 06:00 [pubmed] PHST- 2020/07/18 06:00 [medline] PHST- 2019/03/27 06:00 [entrez] PHST- 2020/05/01 00:00 [pmc-release] AID - 10.1038/s41422-019-0157-4 [pii] AID - 157 [pii] AID - 10.1038/s41422-019-0157-4 [doi] PST - ppublish SO - Cell Res. 2019 May;29(5):391-405. doi: 10.1038/s41422-019-0157-4. Epub 2019 Mar 25.