Abstract
4-1BB (CD137), an inducible costimulatory molecule, strongly enhances the proliferation and effector function of CD8(+) T cells. Since the serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), is involved in a variety of signaling pathways of cellular proliferation, migration, immune responses, and apoptosis, we examined whether 4-1BB signaling activates GSK-3/β-catenin signaling and downstream transcription factors to enhance the proliferation of CD8(+) T cells. 4-1BB signaling induces rapid activation of ERK and IκB degradation, and shows delayed activation of AKT at 24 h post 4-1BB stimulation on anti-CD3 activated T cells. ERK and AKT signals were required for sustained β-catenin levels by inactivating GSK-3, which was also observed with delayed kinetics after 4-1BB stimulation. As a transcriptional partner of β-catenin, 4-1BB signaling decreased levels of FOXO1 and increased levels of stimulatory TCF1 in CD8(+) T cells at 2-3 days but not at early time points after 4-1BB engagement. The enhanced proliferation of CD8(+) T cells due to 4-1BB signaling was completely abolished by treatment with the TCF1/β-catenin inhibitor quercetin. These results show that 4-1BB signaling enhances the proliferation of activated CD8(+) T cells by activating the TCF1/β-catenin axis via the PI3K/AKT/ERK pathway. As effects of 4-1BB on AKT, FOXO1, β-catenin and GSK-3β showed delayed kinetics it is likely that an intervening molecule induced by 4-1BB and ERK signaling in activated T cells is responsible for these effects. These effects were observed on CD8(+) but not on CD4(+) T cells. Moreover, 4-1BB appeared to be unique among several TNFRs tested in inducing increase in stimulatory over inhibitory TCF-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / metabolism*
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Cell Proliferation
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Forkhead Box Protein O1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Hepatocyte Nuclear Factor 1-alpha / genetics
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Hepatocyte Nuclear Factor 1-alpha / metabolism
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Kinetics
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Lymphocyte Activation / genetics
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MAP Kinase Signaling System / genetics*
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Mice
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Mice, Inbred C57BL
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / genetics
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T Cell Transcription Factor 1 / genetics*
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T Cell Transcription Factor 1 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics*
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Hepatocyte Nuclear Factor 1-alpha
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Hnf1a protein, mouse
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I-kappa B Proteins
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T Cell Transcription Factor 1
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Transcription Factors
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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beta Catenin
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
Grants and funding
This work was supported by a research grant from the National Cancer Center, Korea (NCC-1210370-1) and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2005-084-E00001 and 2006-2004212). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.