biostudies-literatureMedina CBNIAID NIH HHSNHLBI NIH HHSWellcome TrustNIGMS NIH HHS1715-1727.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC8363584biostudies-literatureUnknown54(8)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.ImmunityPannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation.PMC8363584R01 GM108989R21 AI139967T32 GM007055R35 GM122542206566/Z/17/ZP01 HL120840R21 AI135455Tung KSElliott MRRavichandran KSPoon IBayliss DAChiu YHLucas CDStremska MEMedina CBDesai BLorenz UMfalsePannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation.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.2021-01-01T00:00:00Z2021 Aug2024-10-18T02:32:53.291Z2024-10-18T02:32:53.291ZS-EPMC83635843428397110.1016/j.immuni.2021.06.014