{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:42:24Z","timestamp":1773657744056,"version":"3.50.1"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2006,10,1]],"date-time":"2006-10-01T00:00:00Z","timestamp":1159660800000},"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":[[2006,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The cyclin-dependent kinase (CDK) inhibitor p27kip1 is an important negative regulator of the cell cycle that sets a threshold for mitogenic signals in T lymphocytes, and is required for T cell anergy in vitro. To determine whether p27kip1 is required for tolerance in vivo, we performed cardiac allograft transplantation under conditions of combined CD28\/CD40L costimulatory blockade. Although this treatment induced long-term allograft survival in wild-type recipients, costimulatory blockade was no longer sufficient to induce tolerance in mice lacking p27kip1. Rejected allografts from p27kip1\u2212\/\u2212 mice contained more CD4+ T lymphocytes and exhibited more tissue damage than allografts from tolerant, wild-type mice. Infiltrating p27kip1-deficient T cells, but not wild-type T cells, exhibited nuclear expression of cyclins E and A, indicating uncontrolled T cell cycle progression in the graft. The failure of tolerance in p27kip1\u2212\/\u2212 mice was also accompanied by markedly increased numbers of allospecific, IFN-\u03b3-producing cells in the periphery, and occurred despite apparently normal regulatory T cell activity. These data demonstrate that the CDK inhibitor p27kip1 enforces the costimulatory requirement for the expansion and differentiation of alloimmune effector T lymphocytes in vivo, and point to CDKs as novel targets for immunosuppressive or tolerance-inducing therapies.<\/jats:p>","DOI":"10.4049\/jimmunol.177.8.5169","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:20:27Z","timestamp":1397848827000},"page":"5169-5176","source":"Crossref","is-referenced-by-count":28,"title":["The Cyclin-Dependent Kinase Inhibitor p27kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade"],"prefix":"10.1093","volume":"177","author":[{"given":"Emily A","family":"Rowell","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Joseph Stokes, Jr. Research Institute, Children\u2019s Hospital of Philadelphia , PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne W","family":"Hancock","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"},{"name":"Joseph Stokes, Jr. Research Institute, Children\u2019s Hospital of Philadelphia , PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D","family":"Wells","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"},{"name":"Joseph Stokes, Jr. Research Institute, Children\u2019s Hospital of Philadelphia , PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2006,10,15]]},"reference":[{"key":"2026020211134417500_R1","first-page":"233","volume-title":"Annu. 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