LAMTOR2 regulates dendritic cell homeostasis through FLT3-dependent mTOR signalling.

Julia M Scheffler,Lukas A Huber,Patrizia Stoitzner,Caroline Herrmann,Alexandra Humenberger,Johanna Blitz,Florian Sparber,Christoph H Tripp,Nikolaus Romani

doi:10.1038/ncomms6138

Julia M Scheffler, Lukas A Huber + Show 7 more

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https://doi.org/10.1038/ncomms6138

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Abstract

The receptor tyrosine kinase Flt3 and its ligand are crucial for dendritic cell (DC) homeostasis by activating downstream effectors including mammalian target of Rapamycin (mTOR) signalling. LAMTOR2 is a member of the Ragulator/LAMTOR complex known to regulate mTOR and extracellular signal-regulated kinase activation on the late endosome as well as endosomal biogenesis. Here we show in mice that conditional ablation of LAMTOR2 in DCs results in a severe disturbance of the DC compartment caused by accumulation of Flt3 on the cell surface. This results in an increased downstream activation of the AKT/mTOR signalling pathway and subsequently to a massive expansion of conventional DCs and plasmacytoid DCs in ageing mice. Finally, we can revert the symptoms in vivo by inhibiting the activation of Flt3 and its downstream target mTOR.

Highlights

The receptor tyrosine kinase Flt[3] and its ligand are crucial for dendritic cell (DC) homeostasis by activating downstream effectors including mammalian target of Rapamycin signalling
It was thought that granulocyte-macrophage colony-stimulating factor (GM-CSF) is the major cytokine promoting DC differentiation, as it allowed for the first time the in vitro generation of DCs from human blood and mouse bone marrow (BM)[16,17,18]
We present evidence that LAMTOR2 is crucial for Flt3dependent DC homeostasis and describe new aspects of LAMTOR complex-mediated late endosomal signalling in immunity

Summary

Introduction

The receptor tyrosine kinase Flt[3] and its ligand are crucial for dendritic cell (DC) homeostasis by activating downstream effectors including mammalian target of Rapamycin (mTOR) signalling. A previously identified human primary immunodeficiency syndrome was ascribed to a point mutation in the LAMTOR2 gene causing a hypomorph allele and reduced protein levels of LAMTOR2 Those patients have severe immunological defects affecting the innate and adaptive immunity, which can be related to a disturbed endosomal- and lysosomal biogenesis. It was shown that the phosphoinositide 3-kinase (PI3K)-AKT-mTOR signalling cascade downstream of Flt[3] controls DC development and expansion[24] Inhibiting this signalling pathway by Rapamycin resulted in an impairment of steady-state DC generation in vivo[25]. Despite the loss of the LAMTOR complex, ligand-induced AKT/mTORC1 signalling downstream of the Flt[3] receptor is unexpectedly increased The outcome of this enhanced mTOR signalling is an expansion of pDCs and conventional DCs (cDCs), which cause a myeloid proliferative syndrome in ageing mice. We present evidence that LAMTOR2 is crucial for Flt3dependent DC homeostasis and describe new aspects of LAMTOR complex-mediated late endosomal signalling in immunity

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