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(deltaCT/deltaCT) mice). DTH responses in sensitized mice were significantly attenuated in TF(deltaCT/deltaCT) 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(deltaCT/deltaCT) mice by transfer of activated CD4(+) OVA-specific TCR transgenic T cells, demonstrating that the defective DTH response in TF(deltaCT/deltaCT) 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(deltaCT/deltaCT) 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.