%0 Journal Article %A Enfu Hui %A Jeanne Cheung %A Jing Zhu %A Xiaolei Su %A Marcus J. Taylor %A Heidi A. Wallweber %A Dibyendu K. Sasmal %A Jun Huang %A Jeong M. Kim %A Ira Mellman %A Ronald D. Vale %T T cell co-stimulatory receptor CD28 is a primary target for PD-1–mediated inhibition %D 2016 %R 10.1101/086652 %J bioRxiv %P 086652 %X 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. %U https://www.biorxiv.org/content/biorxiv/early/2016/11/09/086652.full.pdf