{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T22:14:16Z","timestamp":1782166456459,"version":"3.54.5"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2017,7,1]],"date-time":"2017-07-01T00:00:00Z","timestamp":1498867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Intracellular calcium (Ca2+) mobilization after engagement of the BCR has been proposed to play an important role in B cell development and function. BCR activation causes an initial Ca2+ release from the endoplasmic reticulum that is mediated by inositol 1,4,5-trisphosphate receptor (IP3R) and then triggers store-operated Ca2+ entry once endoplasmic reticulum Ca2+ store is depleted. Store-operated Ca2+ entry has been shown to regulate B cell function but is dispensable for B cell development. By contrast, the function of IP3R-mediated Ca2+ release in B cells remains to be determined. In this study, we generated a B cell\u2013specific IP3R triple-knockout (IP3R-TKO) mouse model and revealed that loss of IP3Rs increased transitional B cell numbers and reduced recirculating mature B cell numbers in bone marrow. In the peripheral tissues, the numbers of conventional B2 B cells and B1 B cells were both significantly decreased in IP3R-TKO mice. Ablation of IP3Rs also dramatically reduced BCR-mediated B cell proliferation and survival. Furthermore, T cell\u2013dependent and T cell\u2013independent Ab responses were altered in IP3R-TKO mice. In addition, deletion of IP3Rs reduced IL-10\u2013producing regulatory B cell numbers and led to defects in NFAT activation, which together resulted in decreased IL-10 secretion. Taken together, our study demonstrated for the first time, to our knowledge, that IP3R-mediated Ca2+ release plays an essential role in regulating B cell development, proliferation, Ab production, and B cell regulatory function in vivo.<\/jats:p>","DOI":"10.4049\/jimmunol.1700109","type":"journal-article","created":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:40:24Z","timestamp":1497487224000},"page":"570-580","source":"Crossref","is-referenced-by-count":39,"title":["Loss of IP3 Receptor\u2013Mediated Ca2+ Release in Mouse B Cells Results in Abnormal B Cell Development and Function"],"prefix":"10.1093","volume":"199","author":[{"given":"Huayuan","family":"Tang","sequence":"first","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsong","family":"Lin","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5653-7654","authenticated-orcid":false,"given":"Feifei","family":"Fan","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Peng","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego School of Medicine , La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Shenzhen University , Shenzhen 518060,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0292-375X","authenticated-orcid":false,"given":"Kunfu","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, Guangdong 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,7,15]]},"reference":[{"key":"2025030614171474800_r1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1146\/annurev.immunol.19.1.595","article-title":"B cell development pathways","volume":"19","author":"Hardy","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"2025030614171474800_r2","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1182\/blood-2006-05-021089","article-title":"Naive recirculating B cells mature simultaneously in the spleen and bone marrow","volume":"109","author":"Cariappa","year":"2007","journal-title":"Blood"},{"key":"2025030614171474800_r3","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nri2656","article-title":"The follicular versus marginal zone B lymphocyte cell fate decision","volume":"9","author":"Pillai","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614171474800_r4","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nri3383","article-title":"Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes","volume":"13","author":"Cerutti","year":"2013","journal-title":"Nat. Rev. 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Biol. Chem."},{"key":"2025030614171474800_r27","doi-asserted-by":"crossref","first-page":"E2797","DOI":"10.1073\/pnas.1402159111","article-title":"Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies","volume":"111","author":"Teodorovic","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030614171474800_r28","doi-asserted-by":"crossref","first-page":"13789","DOI":"10.1073\/pnas.0605944103","article-title":"Testing gene function early in the B cell lineage in mb1-cre mice","volume":"103","author":"Hobeika","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030614171474800_r29","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nri2572","article-title":"Cracking the BAFF code","volume":"9","author":"Mackay","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614171474800_r30","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nri2901","article-title":"The double life of a B-1 cell: self-reactivity selects for protective effector functions","volume":"11","author":"Baumgarth","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614171474800_r31","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.4049\/jimmunol.177.5.2749","article-title":"B-1 B cell development","volume":"177","author":"Hardy","year":"2006","journal-title":"J. Immunol."},{"key":"2025030614171474800_r32","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/ni.1609","article-title":"Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation","volume":"9","author":"Wilker","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025030614171474800_r33","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1146\/annurev-immunol-020711-075032","article-title":"Germinal centers","volume":"30","author":"Victora","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"2025030614171474800_r34","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.it.2007.10.004","article-title":"The \u2018short\u2019 history of regulatory B cells","volume":"29","author":"Mauri","year":"2008","journal-title":"Trends Immunol."},{"key":"2025030614171474800_r35","doi-asserted-by":"crossref","first-page":"4763","DOI":"10.4049\/jimmunol.180.7.4763","article-title":"TLR-activated B cells suppress T cell-mediated autoimmunity","volume":"180","author":"Lampropoulou","year":"2008","journal-title":"J. Immunol."},{"key":"2025030614171474800_r36","doi-asserted-by":"crossref","first-page":"7459","DOI":"10.4049\/jimmunol.0900270","article-title":"The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals","volume":"182","author":"Yanaba","year":"2009","journal-title":"J. Immunol."},{"key":"2025030614171474800_r37","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.immuni.2008.03.017","article-title":"A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses","volume":"28","author":"Yanaba","year":"2008","journal-title":"Immunity"},{"key":"2025030614171474800_r38","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/nri2711","article-title":"The regulation of IL-10 production by immune cells","volume":"10","author":"Saraiva","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614171474800_r39","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1083\/jcb.82.3.755","article-title":"Crosslinking by ligands to surface immunoglobulin triggers mobilization of intracellular 45Ca2+ in B lymphocytes","volume":"82","author":"Braun","year":"1979","journal-title":"J. Cell Biol."},{"key":"2025030614171474800_r40","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-065X.1994.tb00844.x","article-title":"X-linked agammaglobulinemia: new approaches to old questions based on the identification of the defective gene","volume":"138","author":"Conley","year":"1994","journal-title":"Immunol. Rev."},{"key":"2025030614171474800_r41","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/nri801","article-title":"Regulation of B-cell signal transduction by adaptor proteins","volume":"2","author":"Kurosaki","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614171474800_r42","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1126\/science.286.5446.1954","article-title":"An essential role for BLNK in human B cell development","volume":"286","author":"Minegishi","year":"1999","journal-title":"Science"},{"key":"2025030614171474800_r43","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.immuni.2005.01.018","article-title":"Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry","volume":"22","author":"Yu","year":"2005","journal-title":"Immunity"},{"key":"2025030614171474800_r44","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1084\/jem.189.8.1307","article-title":"Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies","volume":"189","author":"O\u2019Keefe","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025030614171474800_r45","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/S0167-7799(97)01060-3","article-title":"Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency","volume":"15","author":"Shultz","year":"1997","journal-title":"Trends Biotechnol."},{"key":"2025030614171474800_r46","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.coi.2007.02.010","article-title":"Control of peripheral B-cell development","volume":"19","author":"Casola","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"2025030614171474800_r47","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1182\/blood-2014-10-606988","article-title":"B-cell survival and development controlled by the coordination of NF-\u03baB family members RelB and cRel","volume":"127","author":"Almaden","year":"2016","journal-title":"Blood"},{"key":"2025030614171474800_r48","doi-asserted-by":"crossref","first-page":"13459","DOI":"10.1073\/pnas.2233620100","article-title":"Normal B-1a cell development requires B cell-intrinsic NFATc1 activity","volume":"100","author":"Berland","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030614171474800_r49","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.immuni.2005.12.013","article-title":"The calcineurin phosphatase complex modulates immunogenic B cell responses","volume":"24","author":"Winslow","year":"2006","journal-title":"Immunity"},{"key":"2025030614171474800_r50","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1074\/jbc.275.5.3479","article-title":"Cyclin D3 compensates for loss of cyclin D2 in mouse B-lymphocytes activated via the antigen receptor and CD40","volume":"275","author":"Lam","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2025030614171474800_r51","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.4049\/jimmunol.1203058","article-title":"Primate B-1 cells generate antigen-specific B cell responses to T cell-independent type 2 antigens","volume":"190","author":"Yammani","year":"2013","journal-title":"J. Immunol."},{"key":"2025030614171474800_r52","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.immuni.2011.01.011","article-title":"Selective utilization of Toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response","volume":"34","author":"Hou","year":"2011","journal-title":"Immunity"},{"key":"2025030614171474800_r53","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/ni833","article-title":"B cells regulate autoimmunity by provision of IL-10","volume":"3","author":"Fillatreau","year":"2002","journal-title":"Nat. Immunol."},{"key":"2025030614171474800_r54","first-page":"3420","article-title":"Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression","volume":"118","author":"Matsushita","year":"2008","journal-title":"J. Clin. 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