Regulation of Memory CD8 T-Cell Differentiation by Cyclin-Dependent Kinase Inhibitor p27^Kip1

Abstract

Induction of potent T-cell memory is the goal of vaccinations, but the molecular mechanisms that regulate the formation of memory CD8 T cells are not well understood. Despite the recognition that controls of cellular proliferation and apoptosis govern the number of memory T cells, the cell cycle regulatory mechanisms that control these key cellular processes in CD8 T cells during an immune response are poorly defined. Here, we have identified the cyclin-dependent kinase inhibitor p27^Kip1 as a critical regulator of the CD8 T-cell homeostasis at all phases of the T-cell response to an acute viral infection in mice. By acting as a timer for cell cycle exit, p27^Kip1 curtailed the programmed expansion of interleukin-2-producing memory precursors and markedly limited the magnitude and quality of CD8 T-cell memory. In the absence of p27^Kip1, CD8 T cells showed superior recall responses shortly after vaccination with recombinant Listeriamonocytogenes. Additionally, we show that p27^Kip1 constrains proliferative renewal of memory CD8 T cells, especially of the effector memory subset. These findings provide critical insights into the cell cycle regulation of CD8 T-cell homeostasis and suggest that modulation of p27^Kip1 could bolster vaccine-induced T-cell memory and protective immunity.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank the flow cytometry facility for sorting cells.

This work was supported by PHS grants AI48785, AI59804, and AI68841 to M. Suresh.