T cell co-stimulatory receptor CD28 is a primary target for PD-1-mediated inhibition

Hui, E.; Cheung, J.; Zhu, J.; Su, X.; Taylor, M. J.; Wallweber, H. A.; Sasmal, D. K.; Huang, J.; Kim, J. M.; Mellman, I.; Vale, R. D.

doi:10.1101/086652

bioRxiv · 10.1101/086652

T cell co-stimulatory receptor CD28 is a primary target for PD-1-mediated inhibition

Hui, E.·Cheung, J.·Zhu, J.·Su, X.·Taylor, M. J.·Wallweber, H. A.·Sasmal, D. K.·Huang, J.·Kim, J. M.·Mellman, I.·Vale, R. D.

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Abstract

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.

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Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I., Vale, R. D.. 2016-11-09. T cell co-stimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. https://doi.org/10.1101/086652

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