PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2.
PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2.
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PD-1 和 BTLA 差异性地调节 T 细胞信号传导，且仅部分通过 SHP1 和 SHP2 调节。
DOI：
10.1083/jcb.201905085
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hui Enfu
中科院分区：
文献类型：
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作者：
Xu Xiaozheng;Hou Bowen;Fulzele Amitkumar;Masubuchi Takeya;Zhao Yunlong;Wu Zijun;Hu Yanyan;Jiang Yong;Ma Yanzhe;Wang Haopeng;Bennett Eric J;Fu Guo;Hui Enfu
免疫抑制受体PD-1的阻断抗体可以刺激T细胞的抗肿瘤活性，但临床受益仅限于一小部分患者。有证据表明，BTLA是一种结构上与PD-1相关的受体，可能有助于抵抗PD-1靶向治疗，但BTLA和PD-1在机制上的不同仍存在争议。在这里，我们比较了BTLA和PD-1招募效应分子和调节T细胞信号的能力。虽然PD-1比更强的磷酸酶SHP1选择性地招募SHP2，但BTLA优先招募SHP1以更有效地抑制T细胞信号转导。与主流观点认为PD-1和BTLA仅通过SHP1/2信号传递相反，我们发现在SHP1/2双缺陷的原代T细胞中，PD-1和BTLA仍然有效地抑制细胞增殖和细胞因子的产生，尽管比野生型T细胞更短暂。因此，PD-1和BTLA可以通过一种独立于SHP1和SHP2的机制抑制T细胞信号转导。
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.