In the context of transplantation, dendritic cells (DCs) can sensitize alloreactive T cells via two pathways. The direct pathway is initiated by donor DCs presenting intact donor MHC molecules. The indirect pathway results from recipient DCs processing and presenting donor MHC as peptide. This simple dichotomy suggests that T cells with direct and indirect allospecificity cannot cross-regulate each other because distinct APCs are involved. In this study we describe a third, semidirect pathway of MHC alloantigen presentation by DCs that challenges this conclusion. Mouse DCs, when cocultured with allogeneic DCs or endothelial cells, acquired substantial levels of class I and class II MHC:peptide complexes in a temperature- and energy-dependent manner. Most importantly, DCs acquired allogeneic MHC in vivo upon migration to regional lymph nodes. The acquired MHC molecules were detected by Ab staining and induced proliferation of Ag-specific T cells in vitro. These data suggest that recipient DCs, due to acquisition of donor MHC molecules, may link T cells with direct and indirect allospecificity.

The physiologic significance of MHCpeptide complex presentation by endothelial cells (ECs) to trafficking T lymphocytes remains unresolved. On the basis of our observation that cognate recognition of ECs enhanced transendothelial migration of antigen-specific T lymphocytes in vitro, we have proposed that by displaying antigenic peptides from the underlying tissue, ECs promote the recruitment of antigen-specific T cells. In this study, we have tested this hypothesis by comparing the trafficking of HYspecific T lymphocytes into antigenic and nonantigenic tissue using in vivo models of T-cell recruitment. Up-regulated expression of H2 molecules presenting endogenous antigen in the peritoneal mesothelium and vessels led to the local recruitment of HY-specific T cells in male, but not female, mice. Intravital microscopy experiments analyzing EC-HYspecific T-cell interactions in the cremasteric vascular bed revealed that cognate recognition of the endothelium results in enhanced diapedesis of T cells into the tissue, while not affecting rolling and adhesion. Our results are consistent with the hypothesis that, under inflammatory conditions, antigen presentation by the endothelium contributes to the development and specificity of T-cell-mediated inflammation by favoring the selective migration of antigen-specific T cells. IntroductionLymphocyte recirculation and the localized recruitment and retention of antigen-specific T cells to sites of inflammation are key events in immune surveillance. While T-lymphocyte recirculation is constitutively regulated and occurs in the absence of inflammation, the development of an immune response depends on the recruitment and retention of specific T cells at antigenic sites, 1 thus minimizing collateral damage caused by non-antigenspecific inflammatory cells. T-cell migration into inflamed tissues involves sustained adhesive interactions with the microvascular endothelium that constitutively expresses major histocompatibility complex (MHC) molecules. Given that endothelial cells (ECs) may display tissue-specific as well as foreign peptides, 1,2 antigen presentation to migrating T cells is likely to occur during the adhesive interactions required for extravasation. The participation of T-cell receptor (TCR)-derived signals in actively promoting T-cell migration has been suggested by the observations that TCR triggering can induce integrin activation 3 and immobilize migrating T cells. 4 In addition, chemokine receptor expression by T cells is susceptible to TCR-mediated modulation. 5 A role for TCR signaling in the control of T-cell motility has also emerged from our recent studies on the functional consequences of antigen presentation by ECs to CD4 ϩ and CD8 ϩ T cells 6,7 in both human and murine systems. In addition, we showed that TCR triggering by the endothelium directly increased T-cell migration by inducing integrin activation. 6 A recent study has provided indirect evidence that insulin-specific clonal CD8 ϩ T cells require cognate recognition of pancreatic microvascular endo...

The type I IFN family includes 14 closely related antiviral cytokines that are produced in response to viral infections. They bind to a common receptor, and have qualitatively similar biological activities. The physiological relevance of this redundancy is still unclear. In this study, we analyzed and compared the effects of two potent antiviral type I IFNs, IFN-α2 and IFN-α8, on the motility of various populations of human T lymphocytes in vitro. In this study, we show that IFN-α2 induces chemokinesis of both CD4+ and CD8+ T cells at various stages of differentiation, and induces functional changes that result in enhanced T cell motility, including up-regulation of the integrins LFA-1 and VLA-4, and subsequently, increased ICAM-1- and fibronectin-dependent migration. In contrast, IFN-α8 did not affect T cell motility, despite having similar antiviral properties and similar effects on the induction of the antiviral protein MxA. However, transcription of other IFN-stimulated genes showed that transcription of these genes is selectively activated by IFN-α2, but not IFN-α8, in T cells. Finally, while the antiviral activity of the two subtypes is inhibited by Abs against the two subunits of the IFN-α receptor, the chemokinetic effect of IFN-α2 is selectively blocked by Abs against the A1 receptor subunit. These observations are consistent with the possibility that subtype-specific intracellular signaling pathways are activated by type I IFNs in T lymphocytes.