The Late Endosomal Adaptor Molecule p14 (LAMTOR2) Regulates TGF beta 1-Mediated Homeostasis of Langerhans Cells

F Sparber, CH Tripp, K Komenda, JM Scheffler, Björn Clausen, LA Huber, N Romani, P Stoitzner

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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 beta 1 (TGF beta 1) pathway, by lowering TGF beta receptor II expression on BMDCs and LCs, as well as surface binding of TGF beta 1 on BMDCs. We conclude that p14 deficiency affects TGF beta 1 sensitivity of LCs, which is mandatory for their homeostasis and subsequently for their immunological function during CHS.
Original languageUndefined/Unknown
Pages (from-to)119-129
Number of pages11
JournalJournal of Investigative Dermatology
Volume135
Issue number1
DOIs
Publication statusPublished - 2015

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