TGN1412, a superagonistic CD28-specific antibody, was shown to require Fc-crosslinking or immobilization as a prerequisite to mediate T cell proliferation and cytokine release in vitro. We used primary human umbilical vein endothelial cells (HUVECs) to study their ability to induce activation of TGN1412-treated T cells. We confirmed that peripheral primary human T cells do not show activation upon stimulation with soluble TGN1412 alone. Nevertheless, co-cultivation of TGN1412-treated T cells with HUVECs induced T cell activation that was further enhanced using cytokine pre-stimulated HUVECs. Unexpectedly, Fc-FcγR interaction was dispensable for endothelial cell-mediated proliferation of TGN1412-treated T cell. Transwell-culture assays showed that TGN1412-treated T cells need direct cell to cell contact to HUVECs to induce proliferation. We found that co-stimulatory ICOS-LICOS interaction between T cells and endothelial cells is critically involved in TGN1412-mediated effects. Blocking LICOS reduced TGN1412-mediated T cell proliferation significantly, whereas recombinant LICOS fully conferred TGN1412-mediated T cell proliferation. Of note, cytokine stimulation enhanced LICOS expression on HUVECs and ICOS-LICOS interaction upregulated ICOS expression on TGN1412-treated T cells. Hence, we provide a model of positive feedback conferred by ICOS-LICOS interaction between TGN1412-treated T cells and endothelial cells.
- Submitted December 23, 2011.
- Accepted April 25, 2012.
- Copyright © 2005 American Society of Hematology