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Ca2+ influx in immune cells is mediated by store-operated Ca2+ entry (SOCE) that results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels. The CRAC channel is formed by three plasma membrane proteins, ORAI1, ORAI2, and ORAI3. Of these, ORAI1 is the best studied and plays important roles in immune function. By contrast, the physiological role of ORAI3 in immune cells remains elusive. We show here that ORAI3 is expressed in many immune cells including macrophages, B cells, and T cells. To investigate ORAI3 function in immune cells, we generated Orai3\u2212\/\u2212 mice. The development of lymphoid and myeloid cells in the thymus and bone marrow was normal in Orai3\u2212\/\u2212 mice, as was the composition of immune cells in secondary lymphoid organs. Deletion of Orai3 did not affect SOCE in B cells and T cells but moderately enhanced SOCE in macrophages. Orai3-deficient macrophages, B cells, and T cells had normal effector functions in vitro. Immune responses in vivo, including humoral immunity (T cell dependent or independent) and antitumor immunity, were normal in Orai3\u2212\/\u2212 mice. Moreover, Orai3\u2212\/\u2212 mice showed no differences in susceptibility to septic shock, experimental autoimmune encephalomyelitis, or collagen-induced arthritis. We conclude that despite its expression in myeloid and lymphoid cells, ORAI3 appears to be dispensable or redundant for physiological and pathological immune responses mediated by these cells.<\/jats:p>","DOI":"10.1085\/jgp.202213104","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T13:35:12Z","timestamp":1658410512000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages"],"prefix":"10.1085","volume":"154","author":[{"given":"Liwei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1369-684X","authenticated-orcid":true,"given":"Lucile","family":"Noyer","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3637-8852","authenticated-orcid":true,"given":"Yin-Hu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony Y.","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5436-1317","authenticated-orcid":true,"given":"Wenyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Saavedra","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7967-2958","authenticated-orcid":true,"given":"Syed T.","family":"Hoda","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5431-8178","authenticated-orcid":true,"given":"Stefan","family":"Feske","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"2022072113345165800_bib1","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.3389\/fimmu.2018.02379","article-title":"Pattern recognition receptors and the host cell death molecular machinery","volume":"9","author":"Amarante-Mendes","year":"2018","journal-title":"Front. 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