Abstracts of the 52nd Workshop for Pediatric Research

Abstract

Plasmacytoid dendritic cells (pDCs) and neurotrophins play an important role in inflammatory diseases. We document, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75NTR by murine and human pDCs. Binding of neurotrophin nerve growth factor (NGF) to p75NTR results in attenuated interferon α secretion in response to Toll-like receptor-9 activation by CpG A, but increased secretion of interleukin (IL) -6 in response to CpG B. In the presence of NGF, murine pDCs stimulated the proliferation of CD4+ T cells and secretion of tumor necrosis factor-α and IL-6 in a p75NTR-dependent manner, whereas CD8+ T cells exhibited the opposite characteristics. These effects were mediated by differential phosphorylation of IRF3, IRF7, IKKα/β and c-Jun. Using a mouse model of ovalbumin-induced asthma, we showed that p75NTR expression by pDCs was essential for mediating allergic inflammation characterized by increased IL-4, IL-5, and IL-13 secretion; eosinophilia; lung tissue inflammation; and Goblet cell hyperplasia. Stimulation of pDCs with NGF exacerbated allergic symptoms. Further, NGF stimulation of human pDCs from patients with asthma aggravated allergen-specific T cell proliferation and IL-5 secretion. Further, NGF treatment of pDCs significantly aggravated Graft-versus-Host disease in a xenotransplantation model and delayed autoimmune diabetes in RIP-CD80GP mice. Our findings underline the global impact of p75NTR modulation on pDCs for immune regulation and its great therapeutic potential.