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.
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.
Kubsch
Sebastian
S
Department of Dermatology, University of Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany.
Graulich
Edith
E
Knop
Jürgen
J
Steinbrink
Kerstin
K
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D060908:CTLA-4 Antigen; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D017635:Clonal Anergy; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates; D016753:Interleukin-10 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018797:Cell Cycle Proteins; D018796:Immunoconjugates; D007376:Interleukin-2; D025521:Tumor Suppressor Proteins; D016753:Interleukin-10; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069594:Abatacept