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 Panx1S205A phenocopied the exacerbated inflammation in Panx1(-/-) mice. These data identify Panx1-dependent Treg:Teff cell communication in restricting airway disease.