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The Cyclin-Dependent Kinase Inhibitor p27^kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade¹

Emily A. Rowell^*, Liqing Wang, Wayne W. Hancock^*, and Andrew D. Wells^2,*,

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Joseph Stokes, Jr. Research Institute, Children’s Hospital of Philadelphia, PA 19104

The cyclin-dependent kinase (CDK) inhibitor p27^kip1 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 p27^kip1 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 p27^kip1. Rejected allografts from p27^kip1–/– mice contained more CD4⁺ T lymphocytes and exhibited more tissue damage than allografts from tolerant, wild-type mice. Infiltrating p27^kip1-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 p27^kip1–/– mice was also accompanied by markedly increased numbers of allospecific, IFN--producing cells in the periphery, and occurred despite apparently normal regulatory T cell activity. These data demonstrate that the CDK inhibitor p27^kip1 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01-AI054643 (to A.D.W.). A.D.W. and W.W.H. are members of the Biesecker Pediatric Liver Disease Center. E.A.R. is supported by National Institutes of Health Training Grant T32-AR007442-18.

² Address correspondence and reprint requests to Dr. Andrew D. Wells, 916F Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: adwells{at}mail.med.upenn.edu

³ Abbreviations used in this paper: CDK, cyclin-dependent kinase; Rb, retinoblastoma protein.

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