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Protease-activated receptor-2 signalling by tissue factor on dendritic cells suppresses antigen-specific CD4(+) T-cell priming

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)219-226
Number of pages8
JournalImmunology
Volume139
Issue number2
Early online date24 Jan 2013
DOIs
Publication statusPublished - Jun 2013

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Abstract

The precise function of tissue factor (TF) expressed by dendritic cells (DC) is uncertain. As well as initiating thrombin generation it can signal through protease-activated receptor 2 (PAR-2) when complexed with factor VIIa. We investigated the expression and function of TF on mouse bone marrow (BM) -derived DC; 20% of BM-derived DC expressed TF, which did not vary after incubation with lipopolysaccharide (LPS) or dexamethasone (DEX). However, the pro-coagulant activity of DEX-treated DC in recalcified plasma was 30-fold less than LPS-treated DC. In antigen-specific and allogeneic T-cell culture experiments, the TF on DEX-treated DC provided a signal through PAR-2, which contributed to the reduced ability of these cells to stimulate CD4+ T-cell proliferation and cytokine production. In vivo, an inhibitory anti-TF antibody and a PAR-2 antagonist enhanced antigen-specific priming in two models where antigen was given without adjuvant, with an effect approximately 50% that seen with LPS, suggesting that a similar mechanism was operational physiologically. These data suggest a novel TF and PAR-2-dependent mechanism on DEX-DC in vitro and unprimed DC in vivo that contributes to the low immunogenicity of these cells. Targeting this pathway has the potential to influence antigen-specific CD4+ T-cell activation.

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