Distinct roles of programmed cell death ligands 1 and 2, based on the type of immunity

Abstract

Abstract Programmed cell death-1 (PD-1) is an immuno-regulatory receptor binding to two ligands, PD-L1 and PD-L2, which are expressed on stimulated antigen presenting cells (APCs). Isolated APCs such as macrophages (Mϕ), dendritic cells (DC), and B cells were cultured with interferon (IFN)-γ, interleukin (IL)-4, and IL-17A, respectively, followed by PD-L1/L2 expression analysis using flow cytometry. Upon stimulation by IFN-γ on all APCs and IL-17A on Mϕ and B cells, respectively, strong and moderate upregulation of PD-L1 expression was observed over unstimulated controls. Only stimulation by IL-4 could upregulate PD-L2 expression on all APCs. Therefore, experiments were performed on murine models, causing 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS), fluorescein isothiocyanate (FITC)-induced CHS, and imiquimod (IMQ)-induced psoriasis-like dermatitis, in order to trigger IFN-γ-mediated T helper (Th)1, IL-4-mediated Th2, and IL-17A-mediated Th17-type responses, respectively. In both Th1 and Th17-type immunity models, ear thickness changes in PD-L1 deficient (PD-L1−/−) mice were more severe than in wild-type (WT) and PD-L2 deficient (PD-L2−/−) mice (PD-L1−/−: 26.6±3.0, WT: 12.0±1.8 and PD-L2−/−: 12.3±1.9 [μm] in DNFB-induced CHS; 9.5±0.7, 6.2±0.4 and 5.7±0.6 [μm] in IMQ-induced psoriasis-like dermatitis [P < 0.01 by the U test], respectively). Thickness changes in PD-L2−/− were more severe than those in the WT and PD-L1−/− mice in the Th2-type immunity model (PD-L2−/−: 10.8±1.0, WT: 3.8±0.6 and PD-L1−/−: 3.6±0.6 [μm], [P < 0.01 by the U test], respectively). Collectively, PD-L1 has predominant roles in Th1 and Th17-type immunity; similarly, PD-L2 for Th2-type immunity.