T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

TLDR

PD‑1 is a coinhibitory receptor that suppresses T cell activation, particularly by inhibiting TCR signaling upon engagement with PD‑L1, and is a key target for cancer immunotherapy. In a biochemical reconstitution system, PD‑1–recruited Shp2 phosphatase preferentially dephosphorylates CD28 rather than the TCR. In intact cells, PD‑1 activation by PD‑L1 preferentially dephosphorylates CD28, demonstrating that PD‑1 suppresses T cell function mainly by inactivating CD28 signaling and highlighting the importance of costimulatory pathways in anti‑PD‑1 therapy.

Abstract

Programmed cell death-1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1-recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.