Immunity
Volume 54, Issue 8, 10 August 2021, Pages 1715-1727.e7
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Article
Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation

https://doi.org/10.1016/j.immuni.2021.06.014Get rights and content
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Highlights

  • The ATP release channel, Panx1, limits the severity of allergic airway inflammation

  • Panx1 on CD4+ T cells is necessary and sufficient for limiting inflammation

  • Treg-Teff crosstalk via Panx1 extracellular nucleotides controls effector response

  • Panx1 activation is dependent on phosphorylation and Salt-inducible kinase (SIK)

Summary

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.

Keywords

Pannexin 1, extracellular ATP, lung, asthma, airway inflammation, T regulatory cell, T effector cell, Salt-inducible kinase, CD4 T cell, adenosine

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