title: CTLA-4-mediated regulatory phenotype of T-cells in tolerant lung recipients.
abstract: Obliterative bronchiolitis (OB) is the major cause of long-term lung allograft loss resulting from an unclear immune process occurring in the absence of the donor's immune cells. The present authors hypothesised that interactions of autologous dendritic cells (DCs) with T-cells could differ in OB patients compared with healthy lung transplant recipients (LTRs). Monocyte-derived DCs from 14 OB and 35 non-OB LTRs were cultured with autologous T-cells. T-regulatory (T(reg)) cells, co-receptors, cytokine production, DC phenotype and indoleamine 2,3-dioxygenase (IDO) expression were assessed by flow cytometry. Experiments were repeated in the presence of Pseudomonas aeruginosa or anti-co-receptor antibodies. DCs from non-OB LTR upregulated T(reg) cells, cytotoxic T-lymphocyte antigen (CTLA)-4 and interleukin (IL)-10. By contrast CD28 and inducible T-cell co-stimulator were downregulated concomitantly to IL-13 and IL-4. Compared to OB, non-OB DCs displayed an immature phenotype with lower CD80 and CD83 and higher IDO levels of expression. Stimulation by P. aeruginosa did not abolish the tolerogenic effects of DCs on non-OB T-cells. Finally, decreased T(reg) cells and IL-10 production were detected when adding anti-CTLA-4 antibodies in non-OB LTR. The present study demonstrates that dendritic cells from nonobliterative bronchiolitis lung transplant recipients induce a tolerant T-cell phenotype which is dependent on cytotoxic T-lymphocyte antigen-4 engagement.
authors.affiliation: Faculty of Medicine, UPRES-EA 3287, University of Mediterranean, France. botturikarine@yahoo.fr
authors.forename: K
authors.initials: K
authors.lastname: Botturi
authors.forename: Y
authors.initials: Y
authors.lastname: Lacoeuille
authors.forename: P
authors.initials: P
authors.lastname: Thomas
authors.forename: S
authors.initials: S
authors.lastname: Boniface
authors.forename: M
authors.initials: M
authors.lastname: Reynaud-Gaubert
authors.forename: A
authors.initials: A
authors.lastname: Magnan
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology*; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human