Investigating the role of DCs in maintaining immune homeostasis, Wang et al. show that LKB1 expression in DCs promotes antitumor immunity by acting as a checkpoint that prevents excessive regulatory immune responses. Partially through negatively regulating mTOR signaling, LKB1 expression maintains DC quiescence (low glycolysis and oxygen consumption; low expression of maturation markers, activation markers, MHC-II), thereby limiting their ability to generate thymic Tregs from precursors or to induce Treg activation and proliferation. LKB1 expression also limits DC production of IL-6, preventing the induction of Th17 (pro-tumor) cell responses.
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.
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 3810
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (3) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (4) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (5) Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (6) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (7) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (8) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (9) Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (10) Department of Pathology, University of Texas (UT) Southwestern Medical Center, Dallas, TX, 75390, USA. (11) Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (12) Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (13) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. hongbo.chi@stjude.org.
