T Cell-Intrinsic and Extrinsic Mechanisms of p27(Kip1) in the Regulation of CD8 T Cell Memory

CD8 T cells exhibit dynamic alterations in proliferation and apoptosis during various phases of the CD8 T cell response, but the mechanisms that regulate cellular proliferation from the standpoint of CD8 T cell memory are not well defined. The cyclin-dependent kinase inhibitor p27(Kip1) functions as a negative regulator of the cell cycle in various cell types including T cells and it has been implicated in regulating cellular processes including differentiation, transcription and migration. Here, we investigated whether p27(Kip1) regulates CD8 T cell memory by T cell-intrinsic or T cell-extrinsic mechanisms, by conditional ablation of p27(Kip1) in T cells or non-T cells. Studies of T cell responses to an acute viral infection show that p27(Kip1) negatively regulates the proliferation of CD8 T cells by T cell-intrinsic mechanisms. However, the enhanced proliferation of CD8 T cells induced by T cell-specific p27(Kip1) deficiency minimally affects the primary expansion or the magnitude of CD8 T cell memory. Unexpectedly, p27(Kip1) ablation in non-T cells markedly augmented the number of high quality memory CD8 T cells by enhancing the accumulation of memory precursor effector cells without increasing their proliferation. Further studies show that p27(Kip1) deficiency in immunizing DCs fail to enhance CD8 T cell memory. Nevertheless, we have delineated the T cell-intrinsic, anti-proliferative activities of p27(Kip1) in CD8 T cells from its role as a factor in non-T cells that restricts the development of CD8 T cell memory. These findings have implications in vaccine development and understanding the mechanisms that maintain T cell homeostasis.