TY - JOUR T1 - BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling JF - bioRxiv DO - 10.1101/669812 SP - 669812 AU - Xiaozheng Xu AU - Amitkumar Fulzele AU - Yunlong Zhao AU - Zijun Wu AU - Yanyan Hu AU - Yong Jiang AU - Yanzhe Ma AU - Haopeng Wang AU - Guo Fu AU - Eric Bennett AU - Enfu Hui Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/14/669812.abstract N2 - 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. ER -