P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus

Faliti, Caterina E.; Gualtierotti, Roberta; Rottoli, Elsa; Gerosa, Maria; Perruzza, Lisa; Romagnani, Andrea; Pellegrini, Giovanni; De Ponte Conti, Benedetta; Rossi, Riccardo L.; Idzko, Marco; Mazza, Emilia M.C.; Bicciato, Silvio; Traggiai, Elisabetta; Meroni, Pier Luigi; Grassi, Fabio

doi:10.1084/jem.20171976

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Journal article

P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus

Faliti, Caterina E. Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
Gualtierotti, Roberta Department of Clinical Science and Community Health, University of Milan, Milan, Italy - Lupus Clinic, IASST-Istituto Gaetano Pini, Milan, Italy
Rottoli, Elsa Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Gerosa, Maria Department of Clinical Science and Community Health, University of Milan, Milan, Italy - Lupus Clinic, IASST-Istituto Gaetano Pini, Milan, Italy
Perruzza, Lisa Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
Romagnani, Andrea Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
Pellegrini, Giovanni Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
De Ponte Conti, Benedetta Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Rossi, Riccardo L. Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi” Milan, Italy
Idzko, Marco Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Vienna, Austria
Mazza, Emilia M.C. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
Bicciato, Silvio Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
Traggiai, Elisabetta Novartis Institute for Biomedical Research, Basel, Switzerland
Meroni, Pier Luigi Department of Clinical Science and Community Health, University of Milan, Milan, Italy - Lupus Clinic, IASST-Istituto Gaetano Pini, Milan, Italy - Istituto Auxologico Italiano, Milan, Italy
Grassi, Fabio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy - Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi,” Milan, Italy

17.01.2019

Published in:

Journal of Experimental Medicine. - 2019, vol. 216, no. 2, p. 317-336

English Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination. P2X7 stimulation promotes caspase-mediated pyroptosis of Tfh cells and controls the development of pathogenic ICOS+ IFN-γ– secreting cells. Circulating Tfh cells from patients with systemic lupus erythematosus (SLE) but not primary antiphospholipid syndrome (PAPS), a nonlupus systemic autoimmune disease, were hyporesponsive to P2X7 stimulation and resistant to P2X7- mediated inhibition of cytokine-driven expansion. These data point to the P2X7 receptor as a checkpoint regulator of Tfh cells; thus, restoring P2X7 activity in SLE patients could selectively limit the progressive amplification of pathogenic autoantibodies, which deteriorate patients’ conditions.

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