Allergic airway inflammation is driven by type-2 CD4⁺ T cell inflammatory responses. We uncover an immunoregulatory role for the nucleotide release channel, Panx1, in T cell crosstalk during airway disease. Inverse correlations between Panx1 and asthmatics and our mouse models revealed the necessity, specificity, and sufficiency of Panx1 in T cells to restrict inflammation. Global Panx1^−/− mice experienced exacerbated airway inflammation, and T-cell-specific deletion phenocopied Panx1^−/− mice. A transgenic designed to re-express Panx1 in T cells reversed disease severity in global Panx1^−/− mice. Panx1 activation occurred in pro-inflammatory T effector (Teff) and inhibitory T regulatory (Treg) cells and mediated the extracellular-nucleotide-based Treg-Teff crosstalk required for suppression of Teff cell proliferation. Mechanistic studies identified a Salt-inducible kinase-dependent phosphorylation of Panx1 serine 205 important for channel activation. A genetically targeted mouse expressing non-phosphorylatable Panx1^S205A phenocopied the exacerbated inflammation in Panx1^−/− mice. These data identify Panx1-dependent Treg:Teff cell communication in restricting airway disease.

过敏性气道炎症是由 2 型 CD4 ⁺ T 细胞炎症反应驱动的。我们揭示了核苷酸释放通道 Panx1 在气道疾病期间 T 细胞串扰中的免疫调节作用。Panx1 和哮喘患者以及我们的小鼠模型之间的负相关性揭示了 T 细胞中 Panx1 限制炎症的必要性、特异性和充分性。全局Panx1 ^-/-小鼠气道炎症加剧，T 细胞特异性缺失表型复制Panx1 ^-/-小鼠。设计用于在 T 细胞中重新表达 Panx1 的转基因逆转了全局Panx1中的疾病严重程度^-/-老鼠。Panx1 激活发生在促炎性 T 效应 (Teff) 和抑制性 T 调节 (Treg) 细胞中，并介导抑制 Teff 细胞增殖所需的基于细胞外核苷酸的 Treg-Teff 串扰。机理研究确定了 Panx1 丝氨酸 205 的盐诱导激酶依赖性磷酸化，对通道激活很重要。表达非磷酸化 Panx1 ^{S205A的基因靶向小鼠表型复制了}Panx1 ^-/-小鼠中加剧的炎症。这些数据确定了 Panx1 依赖性 Treg：Teff 细胞通讯在限制气道疾病中的作用。