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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-\u03b3\u2013secreting 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\u2019 conditions.<\/jats:p>","DOI":"10.1084\/jem.20171976","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T20:15:14Z","timestamp":1547756114000},"page":"317-336","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":116,"title":["P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus"],"prefix":"10.1084","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0487-1914","authenticated-orcid":true,"given":"Caterina E.","family":"Faliti","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera Italiana, Bellinzona, Switzerland 1"},{"name":"Graduate School for 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