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 Tcells 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 (Treg) 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 Treg 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 Treg 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.

Indoleamine 2,3-Dioxygenase in Lung Allograft Tolerance

“…This does not seem to be in line with a report from Botturi and colleagues, who demonstrated that DC generated from BOS patients and stimulated with Pseudomonas aeruginosa extracts expressed less IDO and were less efficient at Treg-cell amplification than DC obtained from stable recipients. 28 However, several differences must be considered when comparing our data and those of Botturi et al, including different culture and stimulation conditions and different methods of IDO expression/activity assessment, which could justify this discrepancy. Nevertheless, data we obtained on IFN-␥-stimulated PBMC seem to suggest that the global increase in IDO activity we detected in BOS plasma should not be ascribed to an increase of enzyme expression by DC.…”

Differences in allergen-induced T cell activation between allergic asthma and rhinitis: Role of CD28, ICOS and CTLA-4

“…It could result from the intrinsic defect in the CTLA-4+ and Treg populations as CTLA-4, known to be involved in tolerance induction [22], could prevent the asthmatic inflammation by inducing T cells to differentiate in T regulatory cells. Recently, we have showed during in vivo studies a lower proportion of Treg cells in blood from severe refractory asthmatics compared to controls, which was even deeper during exacerbations, both in blood and induced sputum [9].…”

Regulatory T cells in lung transplantation—an emerging concept

“…Because this early study was cross-sectional in design, it could not account for the fact that patients with BOS may have lower Treg counts as a direct consequence of higher cumulative and mean levels of calcinurin exposure. These findings have subsequently been confirmed by another group in which foxP3 expression was compared in autologous dendritic cell/peripheral blood mononuclear cells (PBMC) co-cultures in patients with BOS and patients with stable lung function [48]. Induction of foxP3 and production of IL-10 was observed in stable patients, whereas these markers were decreased after co-culture in patients with BOS.…”