1. The late endosomal adaptor molecule p14 (LAMTOR2) regulates TGFβ1-mediated homeostasis of Langerhans cells.
- Author
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Sparber F, Tripp CH, Komenda K, Scheffler JM, Clausen BE, Huber LA, Romani N, and Stoitzner P
- Subjects
- Animals, CD11c Antigen genetics, CD11c Antigen immunology, CD11c Antigen metabolism, Cell Movement immunology, Dermatitis, Contact genetics, Dermatitis, Contact metabolism, Down-Regulation immunology, Endosomes immunology, Endosomes metabolism, Female, Homeostasis immunology, Immune Tolerance immunology, Immunophenotyping, Langerhans Cells metabolism, Male, Mice, Mutant Strains, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases immunology, Protein Serine-Threonine Kinases metabolism, Proteins genetics, Proteins metabolism, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta genetics, Receptors, Transforming Growth Factor beta immunology, Receptors, Transforming Growth Factor beta metabolism, Skin metabolism, Transforming Growth Factor beta1 metabolism, Dermatitis, Contact immunology, Langerhans Cells immunology, MAP Kinase Signaling System immunology, Proteins immunology, Skin immunology, Transforming Growth Factor beta1 immunology
- 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.
- Published
- 2015
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