RT Journal Article
SR Electronic
T1 T cell co-stimulatory receptor CD28 is a primary target for PD-1–mediated inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 086652
DO 10.1101/086652
A1 Enfu Hui
A1 Jeanne Cheung
A1 Jing Zhu
A1 Xiaolei Su
A1 Marcus J. Taylor
A1 Heidi A. Wallweber
A1 Dibyendu K. Sasmal
A1 Jun Huang
A1 Jeong M. Kim
A1 Ira Mellman
A1 Ronald D. Vale
YR 2016
UL http://biorxiv.org/content/early/2016/11/09/086652.abstract
AB Programmed death-1 (PD-1) is a co-inhibitory 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). Here, by titrating the strength of PD-1 signaling in both biochemical reconstitution systems and in T cells, we demonstrate that the coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1- recruited Shp2 phosphatase. We also show that PD-1 colocalizes with the costimulatory receptor CD28 in plasma membrane microclusters but partially segregates from the TCR. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways may play unexpected roles in regulating effector T cell function and therapeutic responses to anti-PD-L1/PD-1.