Human vascular smooth muscle cells lack essential costimulatory molecules to activate allogeneic memory T cells.
OBJECTIVE
The arterial media, populated by vascular smooth muscle cells (VSMC), is an immunoprivileged compartment and, in contrast to the intima or adventitia containing endothelial cells, is generally spared by inflammatory processes, such as arteriosclerosis. To determine mechanisms of medial immunoprivilege, we investigated the ability of human VSMC versus endothelial cells to activate allogeneic T cells in vitro.


RESULTS
Unlike cultured endothelial cells, cultured VSMC do not activate allogeneic memory CD4 or CD8 T cells and fail to effectively support T-cell proliferation to the polyclonal activator, phytohemagglutinin, consistent with a defect in costimulation function. Although many costimulators are comparably expressed on both cell types, endothelial cells but not VSMC basally express OX40 ligand and upregulate inducible costimulator ligand in response to proinflammatory cytokines. OX40 ligand-transduced, but not control- or inducible costimulator ligand-transduced, VSMC acquire the capacity to stimulate allogeneic memory CD4 T cells to produce cytokines and to proliferate in the presence of supplemental l-tryptophan. OX40 ligand overexpression, although not essential, also enhances allogeneic memory CD8 T-cell responses to VSMC after l-tryptophan supplementation.


CONCLUSIONS
The inability of cultured VSMC to activate memory T cells results from a lack of essential costimulators, particularly OX40 ligand, in addition to indoleamine 2,3-dioxygenase-mediated tryptophan depletion.
Departments of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA.
Pei
P
Zhang
Thomas D
TD
Manes
Jordan S
JS
Pober
George
G
Tellides
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D060945:Inducible T-Cell Co-Stimulator Ligand; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology*; D053278:OX40 Ligand / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication; D010835:Phytohemagglutinins / Q000494:pharmacology; D014161:Transduction, Genetic; D014364:Tryptophan / Q000172:deficiency
D015703:Antigens, CD; D016207:Cytokines; C498514:ICOSLG protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D060945:Inducible T-Cell Co-Stimulator Ligand; D018836:Inflammation Mediators; D008934:Mitogens; D053278:OX40 Ligand; D010835:Phytohemagglutinins; C089251:TNFSF4 protein, human; D014364:Tryptophan