{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:25:02Z","timestamp":1788870302093,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,3,11]],"date-time":"2014-03-11T00:00:00Z","timestamp":1394496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Spanish \u201cUTE for CIMA"},{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"crossref","award":["SAF2006-07818"],"award-info":[{"award-number":["SAF2006-07818"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"crossref","award":["SAF2009-11538"],"award-info":[{"award-number":["SAF2009-11538"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"crossref","award":["SAF2012-35455"],"award-info":[{"award-number":["SAF2012-35455"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Carlos III Institute of Health","award":["CB06\/04\/0067"],"award-info":[{"award-number":["CB06\/04\/0067"]}]},{"name":"Spanish Ministry of Science and Innovation & the European Union","award":["PTQ-10-04247"],"award-info":[{"award-number":["PTQ-10-04247"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2014,5]]},"abstract":"\n Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pH\n i<\/jats:sub>\n ). Subsequent pH\n i<\/jats:sub>\n regulation may involve HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n extrusion through Cl\n \u2212<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n exchangers and\/or Na\n +<\/jats:sup>\n \u2010HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n co\u2010transporters with acid\u2010loading capability. Abnormalities in these mechanisms could result in immune dysfunctions, as suggested by the CD8\n +<\/jats:sup>\n T\u2010cell expansion encountered in mice lacking Ae2 (a widely expressed acid loader with electroneutral and Na\n +<\/jats:sup>\n \u2010independent Cl\n \u2212<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n anion\u2010exchange activity). Here we report that CD8\n +<\/jats:sup>\n T\u00a0cells but not CD4\n +<\/jats:sup>\n T\u00a0cells or other lymphocyte populations, are crucially dependent on Ae2 for pH\n i<\/jats:sub>\n regulation. While total lymphocytes (including isolated CD4\n +<\/jats:sup>\n T\u00a0cells) exhibit Ae1 expression and Na\n +<\/jats:sup>\n \u2010HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n co\u2010transport with acidifying potential, CD8\n +<\/jats:sup>\n T\u00a0cells lack these acid\u2010loading mechanisms. In Ae2\u2010KO mice, CD4\n +<\/jats:sup>\n but not CD8\n +<\/jats:sup>\n T\u00a0cells upregulate these potential Ae2 surrogates. As a consequence, Ae2\u2010KO CD8\n +<\/jats:sup>\n T\u00a0cells exhibit alkalinized pH\n i<\/jats:sub>\n , and dramatically increase their pH\n i<\/jats:sub>\n upon CD3 stimulation. Moreover, stimulated Ae2\u2010deficient CD8\n +<\/jats:sup>\n T\u00a0cells show enhanced intracellular production of IL\u20102 and membrane expression of its receptor IL\u20102R\u03b1, together with increased cell proliferation and activation. These findings demonstrate that CD8\n +<\/jats:sup>\n T\u00a0cells are critically dependent on Ae2 for pH\n i<\/jats:sub>\n homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8\n +<\/jats:sup>\n T\u2010cell responses.\n <\/jats:p>","DOI":"10.1002\/eji.201344218","type":"journal-article","created":{"date-parts":[[2014,2,11]],"date-time":"2014-02-11T01:42:47Z","timestamp":1392082967000},"page":"1341-1351","source":"Crossref","is-referenced-by-count":31,"title":["Anion exchanger 2 is critical for CD8\n +<\/sup>\n T\u00a0cells to maintain pH\n i<\/sub>\n homeostasis and modulate immune responses"],"prefix":"10.1002","volume":"44","author":[{"given":"Axel R.","family":"Concepcion","sequence":"first","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"January T.","family":"Salas","sequence":"additional","affiliation":[{"name":"Department of Surgery Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarai","family":"Sarvide","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"S\u00e1ez","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Departments of Immunology Mayo Clinic College of Medicine Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Portu","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas M.","family":"Banales","sequence":"additional","affiliation":[{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"},{"name":"Ikerbasque Biodonostia Institute San Sebastian Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Herv\u00e1s\u2010Stubbs","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald P. J.","family":"Oude Elferink","sequence":"additional","affiliation":[{"name":"Tytgat Institute for Liver and Intestinal Research Academic Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Prieto","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan F.","family":"Medina","sequence":"additional","affiliation":[{"name":"Center for Applied Medical Research (CIMA) Clinic and School of Medicine University of Navarra Pamplona Spain"},{"name":"CIBERehd the \u201cCarlos III\u201d Institute of Health Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,3,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2820"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.028563"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00037.2007"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20081634"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-003-1180-2"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.029454"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.13.7835"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1951"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.05.080"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3439"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.051096"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb05226.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M509734200"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.02.020"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.11.027"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-012-9362-7"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510250104"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)90735-U"},{"key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"17092","DOI":"10.1016\/S0021-9258(18)37502-1","article-title":"Cloning and characterization of a murine band 3\u2010related cDNA from kidney and from a lymphoid cell line","volume":"263","author":"Alper S. 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