Regulation of PD‐1, PD‐L1, and PD‐L2 expression during normal and autoimmune responses

Abstract

Newer members of the B7‐CD28 superfamily include the receptor PD‐1 and its two ligands, PD‐L1 and PD‐L2. Here, we characterize the expression of PD‐1, PD‐L1, and PD‐L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non‐obese diabetic (NOD) mice and brain from mice with experimental autoimmune encephalomyelitis (EAE). In naive mice, proteiexpression of PD‐1, PD‐L1, and PD‐L2 was detected in the thymus, while PD‐1 and PD‐L1 were detected in the spleen. PD‐L1, but not PD‐L2, was also detected at low levels on cardiac endothelium, pancreatic islets, and syncyciotrophoblasts in the placenta. In pre‐diabetic NOD mice, PD‐1 and PD‐L1 were expressed on infiltrating cells in the pancreatic islets. Furthermore, PD‐L1 was markedly up‐regulated on islet cells. In brains from mice with EAE, PD‐1, PD‐L1, and PD‐L2 were expressed on infiltrating inflammatory cells, and PD‐L1 was up‐regulated on endothelium within EAE brain. The distinct expression patterns of PD‐L1 and PD‐L2 led us to compare their transcriptional regulation in STAT4–/–, STAT6–/–, or NF‐κB p50–/–p65+/– dendritic cells (DC).PD‐L2, but not PD‐L1, expression was dramatically reduced in p50–/–p65+/– DC. Thus, PD‐L1 and PD‐L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level.

Interferon regulatory factor‐1 is prerequisite to the constitutive expression and IFN‐γ‐induced upregulation of B7‐H1 (CD274)

“…Antibodies specific for IRF-1 and IRF-2 were purchased from Cell Signaling Technology (Beverly, MA). [c-32 P]-ATP and poly(dIdC) 2 were obtained from Amersham Biosciences (Piscataway, NJ). PE-conjugated streptavidin was obtained from Jackson ImmunoResearch (West Grove, PA).…”

Alternatively activated macrophages in helminth infections

“…Costimulatory molecules are important regulators of T cell activation, with B7-1 and B7-2 on APCs interacting with the T cell ligands CD28, to provide positive signals [34], or CTLA-4, to provide negative signals [35]. Two other B7 family members are programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), both of which bind PD-1 [36]. Recent studies suggest that these cell surface molecules may be important in macrophagemediated T cell suppression.…”

Association between a PD-1 gene polymorphism and antisperm antibody-related infertility in Iranian men

“…Recent study by Valentina Dal Secco et al demonstrated that mouse testis sertoli cells express elevated level of PD-1 ligand in vitro, by IFN γ treatment [25] To our knowledge, our study is the first investigation of the contribution of PD-1 in male ASA-related infertility in human subjects. This study raises more interest for further investigation to the mechanism of PD-1/PD-1 ligand interaction in the development of ASA-related infertility.…”

“…PD-1 also implicates in negative selection [22], and is crucial for regulation of self-reactive T cells that escape negative selection in the periphery [22]. Studies in mouse models of autoimmune disease have revealed that PD-1: PD-1 ligand interaction not only is important in the inhibition of the primary phase of T cell activation and expansion, but also modulates T cell effector functions upon antigen reencounter [25]. Together, these are indicating the key role of PD-1/PD1ligand ligand interaction in the maintenance of central and peripheral tolerance.…”