Regulation of memory CD8 T-cell differentiation by cyclin-dependent kinase inhibitor p27Kip1

Mol Cell Biol. 2010 Nov;30(21):5145-59. doi: 10.1128/MCB.01045-09. Epub 2010 Aug 30.

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 Listeria monocytogenes. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Viral / administration & dosage
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / physiology
  • Cell Cycle / immunology
  • Cell Differentiation / immunology
  • Cyclin-Dependent Kinase Inhibitor p27 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / immunology*
  • Cyclin-Dependent Kinase Inhibitor p27 / physiology
  • Immunologic Memory / physiology*
  • Interleukin-2 / biosynthesis
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Precursor Cells, T-Lymphoid / cytology
  • Precursor Cells, T-Lymphoid / immunology
  • Precursor Cells, T-Lymphoid / physiology

Substances

  • Antigens, Viral
  • Cdkn1b protein, mouse
  • Interleukin-2
  • Cyclin-Dependent Kinase Inhibitor p27