Differential involvement of programmed cell death ligands in skin immune responses.

Abstract

Programmed cell death-1 (PD-1) is an immuno-regulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with interferon (IFN)-γ, interleukin (IL)-4, or IL-17A and expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed upon IFN-γ stimulation of both antigen-presenting cells, as well as in response to IL-17A stimulation of macrophages compared to unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including 2,4-dinitrofluorobenzene-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-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, changes in ear thickness were more severe in PD-L1-deficient mice than in wild-type or PD-L2-deficient mice. In the Th2-type immunity model, changes in thickness in PD-L2-deficient mice were more severe than that in wild-type or PD-L1-deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, while PD-L2 is involved in Th2-type immunity.