The cyclin-dependent kinase inhibitor p27kip1 is required for transplantation tolerance induced by costimulatory blockade.
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 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 p27kip1. Rejected allografts from p27kip1-/- 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-/- mice was also accompanied by markedly increased numbers of allospecific, IFN-gamma-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.
Rowell
Emily A
EA
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Wang
Liqing
L
Hancock
Wayne W
WW
Wells
Andrew D
AD
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D023001:Transplantation Tolerance
D018106:CD28 Antigens; C493961:Cdkn1b protein, mouse; D023201:CD40 Ligand; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases