title: The late endosomal adaptor molecule p14 (LAMTOR2) regulates TGFβ1-mediated homeostasis of Langerhans cells.
abstract: Langerhans cells (LCs), a sub-population of dendritic cells (DCs) in the skin, participate in the regulation of immunity and peripheral tolerance. The adaptor molecule p14 is part of the late endosomal/lysosomal adaptor and mitogen-activated protein kinase and mammalian target of rapamycin (mTOR) activator/regulator (LAMTOR) complex, which mediates the activation of lysosome-associated extracellular signaling-regulated kinase (ERK) and the mTOR cascade. In previous work, we demonstrated that CD11c-specific deficiency of p14 disrupts LC homeostasis by affecting the LAMTOR-mediated ERK and mTOR signaling. In this study, we extended our analysis on p14 deficiency specifically in LCs. Langerin-specific ablation of p14 caused a complete loss of LCs, accompanied by an increased maturational phenotype of LCs. The absence of LCs in p14-deficient mice reduced contact hypersensitivity (CHS) responses to the contact sensitizer trinitrochlorobenzene. Analysis using bone marrow-derived DCs (BMDCs) revealed that p14 deficiency in DCs/LCs interfered with the LC-relevant transforming growth factor β1 (TGFβ1) pathway, by lowering TGFβ receptor II expression on BMDCs and LCs, as well as surface binding of TGFβ1 on BMDCs. We conclude that p14 deficiency affects TGFβ1 sensitivity of LCs, which is mandatory for their homeostasis and subsequently for their immunological function during CHS.
authors: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
authors: Florian
authors: F
authors: Sparber
authors: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
authors: Christoph H
authors: CH
authors: Tripp
authors: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
authors: Kerstin
authors: K
authors: Komenda
authors: Division of Cell Biology, Biocenter Innsbruck, Innsbruck, Austria.
authors: Julia M
authors: JM
authors: Scheffler
authors: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors: Björn E
authors: BE
authors: Clausen
authors: Division of Cell Biology, Biocenter Innsbruck, Innsbruck, Austria.
authors: Lukas A
authors: LA
authors: Huber
authors: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
authors: Nikolaus
authors: N
authors: Romani
authors: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria. Electronic address: patrizia.stoitzner@i-med.ac.at.
authors: Patrizia
authors: P
authors: Stoitzner
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; C426009:LAMTOR2 protein, mouse; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II