Endothelial cell-induced resistance to cyclosporin A in human peripheral blood T cells requires contact-dependent interactions involving CD2 but not CD28.
The ability of cultured human endothelial cells (EC) to activate resting T cells depends on signals provided by EC that augment T cell IL-2 synthesis. EC-mediated augmentation of IL-2 secretion by PHA-activated T cells is resistant to inhibition by cyclosporin A (CsA) or by ascomycin. Specifically, the 50% inhibitory dose of these drugs is increased over 100-fold in the presence of EC. Although rapamycin also inhibits IL-2 secretion, there is no effect of EC on the sensitivity of T cells to this drug. Resistance to CsA requires cell contact between the EC and T cells and develops 8 h after initiation of coculture. Experiments with blocking Abs implicate T cell CD2 and its endothelial cell ligands, both LFA-3 and CD59, but not T cell CD28 and its putative ligands, in EC-induced resistance to CsA. However, CD2 signals are not sufficient to induce resistance to CsA, and other EC signals remain to be identified. These observations suggest that interactions of graft EC with host T cells may contribute to CsA-resistant reactions in vivo.
Karmann
K
K
Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, Yale School of Medicine, New Haven, CT 06536.
Pober
J S
JS
Hughes
C C
CC
D000818:Animals; D018801:CD2 Antigens / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004351:Drug Resistance / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D011090:Polyenes / Q000494:pharmacology; D020123:Sirolimus; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology
D018801:CD2 Antigens; D018106:CD28 Antigens; D007376:Interleukin-2; D011090:Polyenes; D016572:Cyclosporine; C058028:immunomycin; D020123:Sirolimus; D016559:Tacrolimus