Endothelial cells augment the suppressive function of CD4+ CD25+ Foxp3+ regulatory T cells: involvement of programmed death-1 and IL-10.

Blood endothelial cells (ECs) act as gatekeepers to coordinate the extravasation of different T cell subpopulations. ECs express defined panels of adhesion molecules, facilitating interaction with blood circulating T cells. In addition to the mere adhesion, this cellular interaction between ECs and transmigrating T cells may also provide signals that affect the phenotype and function of the T cells. To test the effects of ECs on regulatory T cells (T(reg)) we set up cocultures of freshly isolated murine T(reg) and primary ECs and assessed the phenotype and function of the T(reg). We show that T(reg) upregulate programmed death-1 (PD-1) receptor expression, as well IL-10 and TGF-beta secretion after contact to ECs. These changes in phenotype were accompanied by an increased suppressive capacity of the T(reg). Blockade of the PD-1 and/or the IL-10 secretion in the in vitro suppression assays abrogated the enhanced suppressive capacity, indicating relevance of these molecules for the enhanced suppressive activity of T(reg). In aggregate, our data show, that ECs increase the immunosuppressive potential of activated T(reg) by upregulation of PD-1 and stimulation of the production of high levels of IL-10 and TGF-beta. Therefore, one can speculate that T(reg) during transendothelial transmigration become "armed" for their suppressive function(s) to be carried out in peripheral tissues sites.