{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T14:09:03Z","timestamp":1776002943457,"version":"3.50.1"},"reference-count":34,"publisher":"Proceedings of the National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,7,9]]},"abstract":"<jats:p>The calcium-dependent phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T cells (NFAT) are important regulators of inducible gene expression in multiple cell types. In T cells, calcineurin-NFAT signaling represents a critical event for mediating cellular activation and the immune response. The widely used immunosuppressant agents cyclosporin and FK506 are thought to antagonize the immune response by directly inhibiting calcineurin-NFAT signal transduction in lymphocytes. To unequivocally establish the importance of calcineurin signaling as a mediator of the immune response, we deleted the gene encoding the predominant calcineurin isoform expressed in lymphocytes,<jats:italic>calcineurin A\u03b2<\/jats:italic>(<jats:italic>CnA\u03b2<\/jats:italic>).<jats:italic>CnA\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice were viable as adults, but displayed defective T cell development characterized by fewer total CD3 cells and reduced CD4 and CD8 single positive cells. Total peripheral T cell numbers were significantly reduced in<jats:italic>CnA\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice and were defective in proliferative capacity and IL-2 production in response to PMA\/ionomycin and T cell receptor cross-linking.<jats:italic>CnA\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice also were permissive to allogeneic tumor-cell transplantation<jats:italic>in vivo<\/jats:italic>, similar to cyclosporin-treated wild-type mice. A mechanism for the compromised immune response is suggested by the observation that<jats:italic>CnA\u03b2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>T cells are defective in stimulation-induced NFATc1, NFATc2, and NFATc3 activation. These results establish a critical role for CnA\u03b2 signaling in regulating T cell development and activation<jats:italic>in vivo<\/jats:italic>.<\/jats:p>","DOI":"10.1073\/pnas.152665399","type":"journal-article","created":{"date-parts":[[2002,7,28]],"date-time":"2002-07-28T22:26:28Z","timestamp":1027895188000},"page":"9398-9403","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":161,"title":["Defective T cell development and function in<i>calcineurin<\/i>A\u03b2-deficient mice"],"prefix":"10.1073","volume":"99","author":[{"given":"Orlando F.","family":"Bueno","sequence":"first","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039"}]},{"given":"Eric B.","family":"Brandt","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039"}]},{"given":"Marc E.","family":"Rothenberg","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 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