Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1

Eur J Immunol. 2003 Jul;33(7):1988-97. doi: 10.1002/eji.200323600.


We have previously shown that human IL-10-treated dendritic cells (DC) induce an antigen-specific anergy in CD4+ T lymphocytes. These anergic T cells are characterized by an inhibited proliferation, a reduced production of IL-2, and additionally display antigen-specific suppressor activity. In this study we investigated the mechanisms underlying the anergic state and regulatory function of these T cells. We did not observe enhanced rates of programmed cell death of anergic CD4+ suppressor T cells compared to T cells stimulated with mature DC. Cell cycle analysis by DNA staining and Western blot experiments revealed an arrest of anergic CD4+ T suppressor cells in the G1 phase. High levels of the IL-2-dependent cyclin-dependent kinase (cdk) inhibitor p27Kip1 were found in anergic CD4+ suppressor T cells resulting in an inhibited activation of retinoblastoma protein and an arrest of cell cycle progression in the G1 phase. Addition of IL-2, but not blocking of the CTLA-4 pathway restored the proliferation of the suppressor T cells. In contrast, both treatments induced a down-regulation of p27Kip1 and acomplete inhibition of the antigen-specific regulatory function as demonstrated by high proliferation and enhanced IFN-gamma production of co-cultured T cells. Further experiments demonstrated that p27Kip-expressing regulatory CD4+CD25+ T cells did not contribute to induction of T cell anergy in this model. Our data show that regulatory function of anergic CD4+ suppressor T cells is associated with an arrest in the G1 phase of the cell cycle mediated by increased levels of the IL-2- and CTLA-4-dependent cdk inhibitor p27Kip1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Antigens, CD
  • Antigens, Differentiation / metabolism
  • Apoptosis / physiology
  • CTLA-4 Antigen
  • Cell Cycle Proteins / metabolism
  • Cell Division / physiology
  • Clonal Anergy
  • Cyclin-Dependent Kinase Inhibitor p27
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Humans
  • Immunoconjugates*
  • Interleukin-10 / metabolism*
  • Interleukin-2 / metabolism*
  • T-Lymphocytes / immunology*
  • Tumor Suppressor Proteins / metabolism


  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cell Cycle Proteins
  • Immunoconjugates
  • Interleukin-2
  • Tumor Suppressor Proteins
  • Interleukin-10
  • Cyclin-Dependent Kinase Inhibitor p27
  • Abatacept