Programmed Death Ligand 1 (Pd-L1) Plays A Vital Part In Dc Tolerogenicity Induced By Ifn-Gamma

Interferon-gamma (IFN-gamma) is the sole representative of type II IFNs, with well recognized role in numerous inflammatory processes. Lately, its significant pleiotropic nature has been recognized in many scenarios, where IFN-gamma contributes to maintenance or induction of tolerogenic responses in context of various immune cell types. In this manuscript we demonstrate, that IFN-gamma-mediated induction of programmed death ligand 1 (PD-L1) on human monocyte-derived dendritic cells (DCs) represents an important tolerogenic aspect in immunological network of type II IFNs. When fully differentiated, immature DCs were treated with increasing concentrations of IFN-gamma there was no sign of maturation, as revealed by CD80, CD83 and CD86 expression. In terms of co-stimulatory receptor response, we did observe a dose-dependent increase in CD40 expression. Phenotypic analysis of inhibitory molecules revealed that PD-L1 expression is particularly sensitive to IFN-gamma, as its expression can be induced almost 10-fold in comparison to non-treated DCs. Functional analysis of such PD-L1(high) DCs revealed significant immunosuppressive properties in a mixed lymphocyte reaction with whole or memory CD4(+) T cells. When IFN-gamma treated DCs were co-cultured with naive CD4(+)CD45RA(+) T cells, they induced an increased percentage of CD4(+)CD25(+)CD127(-)FoxP3(+) Tregs. Inhibition of PD-1/PD-L1 axis using neutralizing anti-PD-L1 mAbs, reversed the immunosuppressive effect of IFN-gamma-treated DCs to suppress CD4(+) T cell proliferation and to induce Tregs. In summary, our findings demonstrate the importance of IFN-gamma-mediated tolerogenic effects, exerted on DCs by inducing increased expression of PD-L1, which enhances their regulatory function.