title: ATP-gated ionotropic P2X7 receptor controls follicular T helper cell numbers in Peyer's patches to promote host-microbiota mutualism.
abstract: Microbial colonization of the gut induces the development of gut-associated lymphoid tissue (GALT). The molecular mechanisms that regulate GALT function and result in gut-commensal homeostasis are poorly defined. T follicular helper (Tfh) cells in Peyer's patches (PPs) promote high-affinity IgA responses. Here we found that the ATP-gated ionotropic P2X7 receptor controls Tfh cell numbers in PPs. Lack of P2X7 in Tfh cells enhanced germinal center reactions and high-affinity IgA secretion and binding to commensals. The ensuing depletion of mucosal bacteria resulted in reduced systemic translocation of microbial components, lowering B1 cell stimulation and serum IgM concentrations. Mice lacking P2X7 had increased susceptibility to polymicrobial sepsis, which was rescued by Tfh cell depletion or administration of purified IgM. Thus, regulation of Tfh cells by P2X7 activity is important for mucosal colonization, which in turn results in IgM serum concentrations necessary to protect the host from bacteremia.
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Proietti
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland; Novartis Institute for Biomedical Research, Fabrickstrasse 2, 4002 Basel, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cornacchione
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Rezzonico Jost
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Romagnani
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
authors.forename: Caterina Elisa
authors.initials: CE
authors.lastname: Faliti
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Perruzza
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Rosita
authors.initials: R
authors.lastname: Rigoni
authors.affiliation: Fondazione Filarete, Viale Ortles 22/4, 20139 Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy; Unit of Gastroenterology 2, Fondazione IRCCS Ca' Granda, Ospedale Policlinico di Milano, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.affiliation: Department of Veterinary Medical Sciences, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Preziuso
authors.affiliation: Novartis Institute for Biomedical Research, Fabrickstrasse 2, 4002 Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Brannetti
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.affiliation: Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Institute of Microbiology, ETH Zurich, HCI F 413 Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.affiliation: Novartis Institute for Biomedical Research, Fabrickstrasse 2, 4002 Basel, Switzerland.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland; Department of Medical Biotechnology and Translational Medicine, University of Milan, Via G.B. Viotti 3/5, 20133 Milan, Italy. Electronic address: fabio.grassi@irb.usi.ch.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016470:Bacteremia / Q000276:immunology; D020022:Genetic Predisposition to Disease; D018858:Germinal Center / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000276:immunology / Q000382:microbiology; D013559:Symbiosis / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D007070:Immunoglobulin A; D007075:Immunoglobulin M; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate