Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0607353 on January 7, 2008

Published online before print January 7, 2008
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(Journal of Leukocyte Biology. 2008;83:902-911.)
© 2008 by Society for Leukocyte Biology

The cytoplasmic domain of tissue factor in macrophages augments cutaneous delayed-type hypersensitivity

Jim Apostolopoulos1, Michael J. Hickey, Laveena Sharma, Piers Davenport, Leon Moussa, Will G. James, Julia L. Gregory, A. Richard Kitching, Ming Li and Peter G. Tipping

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia

1 Correspondence: Department of Medicine, Level 5, Block E, Monash Medical Centre, 246 Clayton Rd., Clayton Victoria, 3168 Australia. E-mail: jim.apostolopoulos{at}med.monash.edu.au

In addition to its procoagulant role, tissue factor (TF) has important coagulation-independent roles, including in inflammation. The cytoplasmic domain of TF has been implicated in some of these coagulation-independent roles, particularly cell signaling. To assess the contribution of the cytoplasmic domain of TF to cell-mediated adaptive immunity, the development of cutaneous delayed-type hypersensitivity (DTH) was studied in mice lacking the cytoplasmic domain of TF (TF{delta}CT/{delta}CT mice). DTH responses in sensitized mice were significantly attenuated in TF{delta}CT/{delta}CT mice, and leukocyte-endothelial cell interactions, assessed by intravital microscopy, were impaired significantly. Studies in chimeric mice, created by bone marrow transplantation, showed that the absence of the cytoplasmic domain of TF in leukocytes rather than endothelial cells was responsible for reduced DTH and leukocyte recruitment. DTH responses to OVA could be induced in wild-type mice but not in TF{delta}CT/{delta}CT mice by transfer of activated CD4+ OVA-specific TCR transgenic T cells, demonstrating that the defective DTH response in TF{delta}CT/{delta}CT mice was independent of any defect in T cell activation. Macrophage and neutrophil accumulation and expression of TNF-{alpha} mRNA and phospho-p38-MAPK were reduced significantly in TF{delta}CT/{delta}CT mice, and their macrophages had reduced P-selectin-binding capacity and reduced in vivo emigration in response to MCP-1. These results indicate that leukocyte expression of the cytoplasmic domain of TF contributes to antigen-specific cellular adaptive immune responses via effects on leukocyte recruitment and activation.

Key Words: DTH • coagulation • inflammation • intravital microscopy






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