Research Article

Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses

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Science  10 May 2019:
Vol. 364, Issue 6440, pp. 558-566
DOI: 10.1126/science.aav7062

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Sparing T cells from inhibition

Programmed cell death 1 (PD-1) is an inhibitory receptor that normally keeps T cell immune responses in check. Immunotherapy targeting PD-1 has proven successful for certain types of cancer, but it remains unclear how PD-1 is regulated. Sugiura et al. found that a costimulatory molecule, CD80, can restrict PD-1 function during the activation of T lymphocytes. Binding of CD80 to the PD-1 ligand PD-L1 in cis on primary activated dendritic cells interfered with the ability of PD-L1 to access PD-1 on T cells, which would otherwise have inhibited T cell activation. Functional insights into PD-L1–CD80 interactions may explain the outcomes of anti–PD-1 and anti–PD-L1 cancer therapy.

Science, this issue p. 558

Abstract

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.

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