title: Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity.
abstract: Endothelial cells have been shown to activate T cell responses to alloantigens, triggering transplant rejection. However, they may also play a role in tolerance induction. Using RT-PCR we show here that alloantigen specific CD8(+)CD28(-) T suppressor cells generated in vitro are FOXP3 positive and interact with human endothelial cells. This interaction results in the induction of inhibitory receptors and down-regulation of costimulatory and adhesion molecules, thus rendering endothelial cells tolerogenic. In turn, tolerized endothelial cells elicit the differentiation of CD8(+)CD28(-) FOXP3(+) T suppressor cells. Taken together our data demonstrate a functional and phenotypic overlap between tolerogenic dendritic cells and endothelial cells. Furthermore, alloantigen specific CD8(+)CD28(-) FOXP3(+) T cells, which trigger the upregulation of inhibitory receptors in endothelial cells, are present in the circulation of heart allograft recipients in quiescence as demonstrated by flow cytometry, RT-PCR and luciferase transcription assays. Their detection facilitates the identification of patients who may benefit from partial or complete cessation of immunosuppressive therapy, a goal of obvious importance given the morbidity and mortality associated with chronic immunosuppression. Modulation of endothelial cells in favor of promoting tolerance may be important for long-term survival of organ allografts.
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Manavalan
authors.forename: Seunghee
authors.initials: S
authors.lastname: Kim-Schulze
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.forename: Afzal J
authors.initials: AJ
authors.lastname: Naiyer
authors.forename: George
authors.initials: G
authors.lastname: Vlad
authors.forename: Paolo C
authors.initials: PC
authors.lastname: Colombo
authors.forename: Charles
authors.initials: C
authors.lastname: Marboe
authors.forename: Donna
authors.initials: D
authors.lastname: Mancini
authors.forename: Raffaello
authors.initials: R
authors.lastname: Cortesini
authors.forename: Nicole
authors.initials: N
authors.lastname: Suciu-Foca
mesh_terms: D000328:Adult; D001483:Base Sequence; D018106:CD28 Antigens / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology*; D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000401:mortality; D007519:Isoantigens / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D007519:Isoantigens; C491341:LILRB2 protein, human; C107907:LILRB4 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic