T cells must migrate to encounter antigen-presenting cells and perform their roles in host defense. Here, we found that autocrine stimulation of the purinergic receptor P2Y11 regulates the migration of human CD4 T cells. P2Y11 receptors redistributed from the front to the back of polarized cells where they triggered intracellular cAMP/PKA signals that attenuated mitochondrial metabolism at the back. The absence of P2Y11 receptors at the front of cells resulted in hotspots of mitochondrial metabolism and localized ATP production that stimulated P2X4 receptors, Ca²⁺ influx, and pseudopod protrusion at the front. This regulatory function of P2Y11 receptors depended on their subcellular redistribution and autocrine stimulation by cellular ATP release and was perturbed by indiscriminate global stimulation. We conclude that excessive extracellular ATP—such as in response to inflammation, sepsis, and cancer—disrupts this autocrine feedback mechanism, which results in defective T cell migration, impaired T cell function, and loss of host immune defense.

T 细胞必须迁移以遇到抗原呈递细胞并在宿主防御中发挥作用。在这里，我们发现嘌呤能受体 P2Y11 的自分泌刺激调节人类 CD4 T 细胞的迁移。P2Y11 受体从极化细胞的前部重新分布到后部，在那里它们触发细胞内 cAMP/PKA 信号，从而减弱背部的线粒体代谢。细胞前部缺乏 P2Y11 受体导致线粒体代谢热点和局部 ATP 产生，刺激 P2X4 受体 Ca ²⁺前部涌入，伪足突出。P2Y11 受体的这种调节功能依赖于它们的亚细胞再分布和细胞 ATP 释放的自分泌刺激，并受到不加选择的全局刺激的干扰。我们得出结论，过量的细胞外 ATP（例如对炎症、败血症和癌症的反应）会破坏这种自分泌反馈机制，从而导致 T 细胞迁移缺陷、T 细胞功能受损和宿主免疫防御丧失。