TY - JOUR
T1 - Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation
AU - Medina, Christopher B.
AU - Chiu, Yu Hsin
AU - Stremska, Marta E.
AU - Lucas, Christopher D.
AU - Poon, Ivan
AU - Tung, Kenneth S.
AU - Elliott, Michael R.
AU - Desai, Bimal
AU - Lorenz, Ulrike M.
AU - Bayliss, Douglas A.
AU - Ravichandran, Kodi S.
N1 - Funding Information:
The authors thank members of the Ravichandran laboratory, members of the Pannexin Interest Group at UVA for numerous discussions and critical reading of the manuscript, and Dr. Wenhao Xu for help in developing transgenic and genetically targeted mice. 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). C.D.L. current affiliation is University of Edinburgh Center for Inflammation Research, Queen's Medical Research Institute, Edinburgh BioQuarter. C.B.M. and K.S.R designed experiments. C.B.M. performed experiments. C.D.L. performed in vivo Edu labeling. M.E.S and B.D. generated the Panx1S205A mice. I.P. performed the yeast two-hybrid screen. Y.C. and D.A.B. cloned plasmids and performed the electrophysiology studies. K.S.T. scored the tissue histology slides. M.R.E. and U.M.L. provided key mouse tools and conceptual advice. C.B.M. and K.S.R wrote the manuscript with input from coauthors. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the genomic datasets.
Funding Information:
The authors thank members of the Ravichandran laboratory, members of the Pannexin Interest Group at UVA for numerous discussions and critical reading of the manuscript, and Dr. Wenhao Xu for help in developing transgenic and genetically targeted mice. 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 ). C.D.L. current affiliation is University of Edinburgh Center for Inflammation Research, Queen’s Medical Research Institute, Edinburgh BioQuarter.
Publisher Copyright:
© 2021 The Authors
PY - 2021/8/10
Y1 - 2021/8/10
N2 - 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.
AB - 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.
KW - Pannexin 1, extracellular ATP, lung, asthma, airway inflammation, T regulatory cell, T effector cell, Salt-inducible kinase, CD4 T cell, adenosine
UR - http://www.scopus.com/inward/record.url?scp=85111926391&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2021.06.014
DO - 10.1016/j.immuni.2021.06.014
M3 - Article
C2 - 34283971
AN - SCOPUS:85111926391
SN - 1074-7613
VL - 54
SP - 1715-1727.e7
JO - Immunity
JF - Immunity
IS - 8
ER -