Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation

Abstract

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor–mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon γ, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

“…1,2 Adaptive mechanisms in tumor cells include inflammatory cytokine-induced expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1), 2,3 which is encoded by the gene CD274 . Through its interaction with the corresponding receptor programmed cell death protein 1 (PD-1) on the surface of immune cells, tumor PD-L1 suppresses antitumor immunity in the tumor microenvironment by multiple mechanisms including induction of T cell apoptosis and functional exhaustion.…”

“…Through its interaction with the corresponding receptor programmed cell death protein 1 (PD-1) on the surface of immune cells, tumor PD-L1 suppresses antitumor immunity in the tumor microenvironment by multiple mechanisms including induction of T cell apoptosis and functional exhaustion. 2,4 More recent studies show that PD-L1 expressed in host immune cells including myeloid cells also contribute to suppression of antitumor immunity and immunotherapy. 5–7 Anti-PD-L1 and anti-PD-1 antibody immunotherapies block the immune-suppressive actions of PD-L1/PD-1 to mediate durable responses and have become standard of care for multiple cancer types.…”

Mouse B7-H3 induces antitumor immunity

“…[4][5][6] B7-H1 (PD-L1) and B7-DC (PD-L2) bind the receptor PD-1 on T cells, and inhibit T-cell proliferation and cytokine production. [7][8][9] In support, PD-1-deficient animals suffer from autoimmune disorders, including lupus-like glomerulonephritis, 10 and dilated cardiomyopathy. 11 The newest member of the B7 family, designated B7-H3, was cloned from a human dendritic cell-derived cDNA library.…”

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

“…PD-1 ligand 1 (PD-L1) and PD-1 ligand 2 (PD-L2), members of the B7 superfamily, are ligands for PD-1 [16][17][18][19]. Mouse (m) PD-L1 and PD-L2 share 38% amino acid identity and have extracellular Ig-like domains [4].…”

“…When PD-L1-Ig or PD-L2-Ig fusion proteins were used, inhibition of T cell proliferation and cytokine production by both resting and previously activated CD4 + [DOI 10.1002/eji.200425197] and CD8 + T cells were observed. The proliferative responses of anti-CD3-activated wild-type, but not PD-1-deficient, T cells were inhibited by PD-L1-Ig, indicating that the inhibitory signal was transduced by PD-1 [17]. However, there is also evidence indicating that both PD-L1 and PD-L2 can costimulate T cell responses; i.e.…”