The Cyclin-Dependent Kinase Inhibitor p27kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade

Abstract

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−/− 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-γ-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.

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…CDK1 is the major driver of cell-cycle progression, CDK2 has been shown to be essential for optimal T cell activation and differentiation, and the CDK9 target MCL1 is required for the survival of activated T cells (75,76). Inhibition of CDK2 through p27 Kip1 , a cell-intrinsic inhibitor of CDKs that is expressed in T cells, has been linked to PD1 and CTLA4 signaling, T cell peripheral tolerance, and CD8 T cell memory, highlighting the importance of CDKs in the maintenance of an active immune response (75,(77)(78)(79)). Yet we observed enhancement of antitumor immunity in our studies and no apparent drop in the number of T cells.…”

New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting

“…Ectopic expression of p27 kip1 has been shown to induce anergy (20), whereas CD4 ϩ T cells that lack p27 kip1 are resistant to anergy induced by a costimulatory blockade in vitro (19). Moreover, p27 kip1 -deficient mice are unable to develop donor-specific tolerance to cardiac allografts in response to a costimulatory blockade in vivo (21). Some modes of anergy induction do not require p27 kip1 .…”

Intracellular Signals of T Cell Costimulation

“…These suggest that p27 (kip1) plays a complex and important role in the regulation of cell division and effector function development in CD4 + T cells (65)(66)(67). Besides this, it has been shown that cell cycle re-entry of quiescent T cells is dependent upon CDK2, and inhibition of CDK2 by p27 (kip1) is the principal constraint on S-phase entry in T cells.…”