Functional Consequences of Noncognate Interactions Between CD4+ Memory T Lymphocytes and the Endothelium

Abstract

The recruitment of Ag-specific T cells to sites of inflammation is a crucial step in immune surveillance. Although the molecular interactions controlling T cell extravasation are relatively well characterized, the effects of these events on T cell function are still poorly understood. Using an in vitro model of transendothelial migration of human CD4+ memory T cells, we have investigated the molecular and functional changes induced in T cells that come into contact with the endothelium. First, we show that transendothelial migration is precluded by signals that lead to T cell division. In addition, activation of the transcription factor AP-1, without induction of NF-κB, is observed in T cells after noncognate interactions with endothelial cells (EC), a pattern of transcriptional regulation different from that observed in dividing T cells. Up-regulation of certain adhesion (CD11a, CD49d), activation (CD69), and costimulatory (CD86) receptors accompany these transcriptional events. Most importantly, recently migrated T cells display a faster rate of migration when reseeded onto an EC monolayer. Finally, T cells become hyperresponsive to antigenic challenge after noncognate interactions with the endothelium. These effects appear not to be due to the selection of preactivated T lymphocytes, because they occur also in clonal T cell populations and appear to be mediated by αLβ2 integrin-CD54 interactions. We conclude that CD4+ memory T cell extravasation is accompanied by phenotypic and functional changes induced by the interactions with the EC, which favor tissue infiltration by T cells and their further activation once they reach the antigenic site.

Antigen presentation by the endothelium: a green light for antigen-specific T cell trafficking?

“…Similarly, simultaneous triggering of the TCR and CD28 in primary human CD4 + T cells leads to a relatively long-lasting (3-5 days) loss of migratory ability [46]. In line with these findings, we have recently reported that different transcriptional programmes are activated during T lymphocyte migration versus division [46].…”

“…In support of the view that it would be physiologically disadvantageous that the endothelium could initiate T cell responses, we have observed that cultured T cell clones, which often lose their physiological requirement for B7-mediated costimulation and can thus be stimulated to proliferate by EC, are unable to migrate through antigenic EC monolayers [45]. Similarly, simultaneous triggering of the TCR and CD28 in primary human CD4 + T cells leads to a relatively long-lasting (3-5 days) loss of migratory ability [46]. In line with these findings, we have recently reported that different transcriptional programmes are activated during T lymphocyte migration versus division [46].…”

Anatomical Heterogeneity of Memory CD4+ T Cells Due to Reversible Adaptation to the Microenvironment

“…Alternatively, memory T cells may adopt a more activated phenotype as a result of transendothelial migration, which is a necessary step for entry into extralymphoid sites. In fact, in vitro studies with human memory CD4 ϩ T cells have demonstrated several phenotypic and functional consequences of noncognate interaction with endothelial cells, which included up-regulation of CD49d and hyper-responsiveness to antigenic stimulation (33). Thus, all memory CD4 ϩ T cells could continuously recirculate between lymphoid and extralymphoid compartments, being transiently activated after transendothelial migration and reverting to a resting state after entry into lymphoid organs.…”

Clinical Relevance and IgG Subclass Determination of Non-HLA Antibodies Identified Using Endothelial Cell Precursors Isolated From Donor Blood

“…Endothelial cell activation has been shown to increase expression of adhesion molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule-1, and decrease Fas-ligand expression allowing safe transmigration of activated T cells (25,26). In addition, transmigration through activated endothelium alters the leukocytes themselves, up-regulating costimulatory markers and enhancing effector functions (27)(28)(29)(30)(31). Thus, AECAs differ from HLA-specific antibodies with regard to IgG subclass and possible mechanisms for eliciting rejection.…”