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.

中文翻译：

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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

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，但临床获益仅限于一小部分患者。有证据表明，BTLA（一种与 PD-1 结构相关的受体）可能会导致对 PD-1 靶向治疗的耐药性，但 BTLA 和 PD-1 在机制上有何不同仍存在争议。在这里，我们比较了 BTLA 和 PD-1 招募效应分子和调节 T 细胞信号传导的能力。虽然 PD-1 选择性地招募 SHP2 而不是更强的磷酸酶 SHP1，但 BTLA 优先招募 SHP1 以更有效地抑制 T 细胞信号传导。与 PD-1 和 BTLA 仅通过 SHP1/2 发出信号的主流观点相反，我们发现在 SHP1/2 双缺陷原代 T 细胞中，PD-1 和 BTLA 仍然有效抑制细胞增殖和细胞因子产生，尽管比在野生型 T 细胞中。因此，PD-1 和 BTLA 可以通过独立于 SHP1 和 SHP2 的机制抑制 T 细胞信号传导。