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

TY - JOUR

T1 - Protease-activated receptor-2 signalling by tissue factor on dendritic cells suppresses antigen-specific CD4(+) T-cell priming

AU - Shrivastava, Seema

AU - Ma, Liang

AU - Tham, El-Li

AU - McVey, John H.

AU - Chen, Daxin

AU - Dorling, Anthony

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

KW - CD4(+) T cell

KW - dendritic cell

KW - dexamethasone

KW - protease-activated receptor-2

KW - tissue factor

KW - FACTOR PATHWAY

KW - COAGULATION

KW - INFLAMMATION

KW - EXPRESSION

KW - MATURATION

U2 - 10.1111/imm.12073

DO - 10.1111/imm.12073

M3 - Article

C2 - 23347132

SN - 0019-2805

VL - 139

SP - 219

EP - 226

JO - Immunology

JF - Immunology

IS - 2

ER -