Neurotrophin Receptor p75NTR Regulates Immune Function of Plasmacytoid Dendritic Cells.

Joanna Bandoła,Matthias Kuhn,Sebastian Thieme,Sebastian Brenner,Michelle P Ashton,Ezio Bonifacio,Benjamin Dorschner,Katrin Navratiel,Cornelia Richter,Christian M Hedrich,Malte Von Bonin,Arshad Jamal,Ingo Roeder,Dimitra Alexopoulou,Andreas Dahl,Martin Ryser

doi:10.3389/fimmu.2017.00981

Abstract

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen-presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.

Highlights

Plasmacytoid dendritic cells are a subset of dendritic cells that act at the interface of innate and adaptive immune responses
We report the discovery of a new role for p75 neurotrophin receptor (p75NTR) signaling during Plasmacytoid dendritic cells (pDCs)-mediated immune responses applying models of an allergic asthma, an autoimmune diabetes type I (T1D) and a graft-versus-host disease (GvHD)
Plasmacytoid dendritic cells play a pivotal role in the modulation of immune responses

Summary

INTRODUCTION

Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that act at the interface of innate and adaptive immune responses. As antigen-presenting cells, pDCs modulate the differentiation and activity of T cell subsets, including TH1, TH2, TH17, and regulatory T cells They are primarily linked to the host defense against pathogens and to pathogen adverse effects, . Transgenic disruption of exon III encoding cysteine rich repeat 2–4 destroyed the neurotrophin binding site in mice but produced viable animals (Ex3 mutant) without detectable expression of full length p75NTR [11] Both wild-type and Ex3-mutant mice still express an alternative splice variant of p75NTR lacking exon III and a functional extracellular binding site for neurotrophins [12]. We report the discovery of a new role for p75NTR signaling during pDC-mediated immune responses applying models of an allergic asthma, an autoimmune diabetes type I (T1D) and a GvHD

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT