Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α

John T. Schroeder, Kristin L. Chichester, Anja P. Bieneman

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Functional significance for the αγ2 variant of the high-affinity IgE receptor (Fcε{lunate}RI) reportedly expressed on human dendritic cell subtypes remains poorly understood. Studies show that immature plasmacytoid dendritic cells (pDCs) secrete large quantities of TNF-α and IL-6 when directly stimulated with anti-IgE antibody. This mode of activation, however, reduces Toll-like receptor 9 (TLR9) expression in pDCs and their ability to mount an IFN-α response when subsequently activated with oligodeoxynucleotide containing CpG. Objective: To investigate the mechanisms underlying this IgE-dependent suppression of TLR9 and innate immune responsiveness in pDCs by focusing on autocrine cytokine responses. Methods: pDCs were isolated from blood by using blood dendritic cell antigen 4 selection. Cytokine responses to anti-IgE antibody-dependent and/or CpG-dependent stimulation were measured by using ELISA. TLR9 expression was determined by using quantitative RT-PCR and Western blotting. Results: The time required for downregulating TLR9 expression in pDCs after anti-IgE stimulation correlated with the induction and duration of TNF-α secreted by these cells. Pretreatment of pDCs with recombinant TNF-α (but not IL-6 or IL-10) markedly suppressed TLR9 expression. Functional response to CpG (ie, IFN-α induction) was also inhibited with TNF-α pretreatment (inhibitory concentration50 = ∼200 pg/mL). Finally, an antibody that neutralizes TNF-α activity completely restored TLR9 expression during anti-IgE stimulation and significantly improved IFN-α secretion on subsequent activation with CpG. Conclusion: Autocrine TNF-α secretion resulting from IgE/Fcε{lunate}RI-dependent activation plays a critical role in suppressing TLR9-dependent responses in pDCs that normally promote TH1 activity.

Original languageEnglish (US)
Pages (from-to)486-491
Number of pages6
JournalJournal of Allergy and Clinical Immunology
Volume121
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • IgE
  • IgE receptor
  • Toll-like receptor
  • allergy
  • cytokine
  • dendritic cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α'. Together they form a unique fingerprint.

Cite this