Cyclin-dependent kinase 2 (CDK2) opposes T cell anergy and promotes cardiac allograft rejection (145.41)

Abstract

Abstract T cell differentiation and anergy are linked to the cell cycle, but the molecular basis of this relationship is not understood. Cyclin-dependent kinases (CDK) represent a major class of cell cycle proteins that could potentially regulate T cell function. Using a combination of dominant-negative, shRNA knock-down, and genetic deletion approaches, we show that the TCR/CD28 complex is specifically coupled to the il2 gene through CDK2. Additionally, a chemical genetic approach using CD4+ T cells expressing an analog-sensitive mutant of CDK2 resulted in dose-dependent inhibition of IL-2 by a specific analog inhibitor. Importantly, transient inhibition of CDK2 activity resulted in a stable state of anergy. T cells lacking CDK2 exhibited defective in vivo alloimmune responses, and mice deficient for CDK2 failed to reject cardiac allografts under conditions of limiting CD28 costimulation. Conversely, deletion of the CDK inhibitory protein p27kip1 resulted in resistance to T cell anergy and failed induction of transplantation tolerance in response to costimulatory blockade. These results suggest that CDK2 is a component of a direct signaling pathway from TCR/CD28 to the il2 gene that is required for anergy avoidance, and implicate CDK2 as a potential target for immunosuppressive therapies that may promote immunological tolerance.