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Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation

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journal contribution
posted on 27.08.2021, 01:06 by CB Medina, YH Chiu, ME Stremska, CD Lucas, Ivan PoonIvan Poon, KS Tung, MR Elliott, B Desai, UM Lorenz, DA Bayliss, KS Ravichandran
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.

Funding

This work is supported by grants to K.S.R. from NHLBI (P01HL120840); NIGMS R35GM122542; the Center for Cell Clearance, University of Virginia School of Medicine; the Odysseus Award from the FWO, Belgium; EOS Grant from the FWO (3083753-DECODE); and the NHLBI (P01HL120840) and NIAID (R21 AI139967 and R21 AI135455) to U.M.L. Additional support was received through the NIH T32 Pharmacology Training Grant (T32GM007055) (C.B.M). C.D.L. was supported by The Wellcome Trust (206566/Z/17/Z). Y.C. was supported by the Ministry of Science and Technology Taiwan (108-2320-B-007-007-MY2).

History

Publication Date

10/08/2021

Journal

Immunity

Volume

54

Issue

8

Pagination

1715-1727.e7

Publisher

Elsevier

ISSN

1074-7613

Rights Statement

© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).