T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory

Immunol Cell Biol. 2013 Feb;91(2):120-9. doi: 10.1038/icb.2012.71. Epub 2012 Dec 4.


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 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 dendritic cells 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.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation
  • Clone Cells
  • Cyclin-Dependent Kinase Inhibitor p27 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • Dendritic Cells / metabolism
  • Gene Deletion
  • Immunologic Memory / immunology*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Knockout
  • Phenotype


  • Cyclin-Dependent Kinase Inhibitor p27