p27(Kip1) negatively regulates the magnitude and persistence of CD4 T cell memory

J Immunol. 2012 Dec 1;189(11):5119-28. doi: 10.4049/jimmunol.1201482. Epub 2012 Oct 15.

Abstract

Much is known about the differentiation of naive T cells into distinct lineages of effector cells, but the molecular mechanisms underlying the generation and maintenance of CD4 T cell memory are poorly characterized. Our studies ascribe a novel role for the cell cycle regulator p27(Kip1) as a prominent negative regulator of the establishment and long-term maintenance of Th1 CD4 T cell memory. We demonstrate that p27(Kip1) might restrict the differentiation and survival of memory precursors by increasing the T-bet/Bcl-6 ratio in effector CD4 T cells. By promoting apoptosis and contraction of effector CD4 T cells by mechanisms that are at least in part T cell intrinsic, p27(Kip1) markedly limits the abundance of memory CD4 T cells. Furthermore, we causally link p27(Kip1)-dependent apoptosis to the decay of CD4 T cell memory, possibly by repressing the expression of γ-chain receptors and the downstream effector of the Wnt/β-catenin signaling pathway, Tcf-1. We extend these findings by showing that the antagonistic effects of p27(Kip1) on CD4 T cell memory require its cyclin-dependent kinase-binding domain. Collectively, these findings provide key insights into the mechanisms underlying the governance of peripheral CD4 T cell homeostasis and identify p27(Kip1) as a target to enhance vaccine-induced CD4 T cell memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / immunology*
  • Gene Expression Regulation / immunology*
  • Hepatocyte Nuclear Factor 1-alpha
  • Immunologic Memory / genetics
  • Immunologic Memory / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Proto-Oncogene Proteins c-bcl-6 / immunology
  • Signal Transduction*
  • T Cell Transcription Factor 1 / genetics
  • T Cell Transcription Factor 1 / immunology
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • Wnt Proteins / genetics
  • Wnt Proteins / immunology
  • beta Catenin / genetics
  • beta Catenin / immunology

Substances

  • CTNNB1 protein, mouse
  • Cdkn1b protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • T Cell Transcription Factor 1
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Wnt Proteins
  • beta Catenin
  • Cyclin-Dependent Kinase Inhibitor p27