BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

Xu, X.; Fulzele, A.; Zhao, Y.; Wu, Z.; Hu, Y.; Jiang, Y.; Ma, Y.; Wang, H.; Fu, G.; Bennett, E.; HUI, E.

doi:10.1101/669812

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bioRxiv · 10.1101/669812

BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

Xu, X.·Fulzele, A.·Zhao, Y.·Wu, Z.·Hu, Y.·Jiang, Y.·Ma, Y.·Wang, H.·Fu, G.·Bennett, E.·HUI, E.

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Abstract

T cell-mediated destruction of tumors and virus-infected cells is restricted by co-inhibitory receptors such as programmed cell death protein 1 (PD-1). Monoclonal antibodies blocking PD-1 have produced impressive clinical activity against human cancers, but durable response is limited to a minority of patients. Previous results suggest that B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor structurally related to PD-1, may contribute to the resistance to PD-1 targeted therapy and co-blockade of BTLA can enhance the efficacy of anti-PD-1 immunotherapy. However, the biochemical mechanism by which BTLA represses T cell activity and to what extent the mechanism differs from that of PD-1 is unknown. Here we examine differences in the ability of BTLA and PD-1 to recruit effector molecules and regulate T cell signaling. We show that PD-1 and BTLA recruit different tyrosine phosphatases to regulate either CD28 or T cell antigen receptor (TCR)-signaling cascades. Our data reveal unexpected disparities between two structurally related immune checkpoints and two phosphatase paralogs.

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Xu, X., Fulzele, A., Zhao, Y., Wu, Z., Hu, Y., Jiang, Y., Ma, Y., Wang, H., Fu, G., Bennett, E., HUI, E.. 2019-06-14. BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling. https://doi.org/10.1101/669812

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