title: Induction of inducible NO synthase in bystander human T cells increases allogeneic responses in the vasculature.
abstract: Inducible NO synthase (iNOS) in human T cells is implicated in the pathogenesis of graft arteriosclerosis. Here we analyze the regulation and role of iNOS in human peripheral blood T cells. Allogeneic endothelial cells (EC) or dermal fibroblasts induce iNOS mRNA and protein expression, as well as enzymatic activity in primary human CD8 T cells. Although human EC activate T cells through the presentation of alloantigen, iNOS induction is confined to nonactivated T cells and does not depend on MHC molecules or costimulators. iNOS induction does involve new transcription and depends on NF-kappaB. JAK signaling, initiated during T cell activation, inhibits iNOS expression. Even though iNOS is confined to bystander T cells, inhibition of iNOS activity reduces T cell proliferation in response to allogeneic EC, and addition of low levels of a NO donor rescues T cell responses. Similarly, iNOS is preferentially expressed by nonproliferating T cells within allografted arteries in vivo, and inhibition of iNOS activity reduces the number of activated T cells in these artery segments. These data identify a previously undescribed mechanism for enhanced activation of alloreactive T cells, namely stromal cell-mediated induction of iNOS in bystander T cells.
authors.affiliation: Interdepartmental Program in Vascular Biology and Transplantation, Section of Immunobiology, and Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Choy
authors.forename: Yinong
authors.initials: Y
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
mesh_terms: D024201:Bystander Effect; D002478:Cells, Cultured; D004790:Enzyme Induction; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology
chemical_list: D052247:Nitric Oxide Synthase Type II