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PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2.

The Journal of cell biology (2020-05-22)
Xiaozheng Xu, Bowen Hou, Amitkumar Fulzele, Takeya Masubuchi, Yunlong Zhao, Zijun Wu, Yanyan Hu, Yong Jiang, Yanzhe Ma, Haopeng Wang, Eric J Bennett, Guo Fu, Enfu Hui

Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.

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