Glycogen synthase kinase (GSK)-3 is a protein serine/threonine kinase that regulates differentiation and cell fate in a variety of organisms. This study examined the role of GSK-3 in antigen-specific T cell responses. Using resting T cells from P14 T cell receptor (TCR)-transgenic mice (specific for the lymphocytic choriomeningitis virus and H-2Db), we demonstrated that GSK-3β was inactivated by serine phosphorylation after viral peptide–specific stimulation in vitro. To further investigate the role of GSK-3, we have generated a retroviral vector that expresses a constitutively active form of GSK-3β that has an alanine substitution at the regulatory amino acid, serine 9 (GSK-3βA9). Retroviral transduction of P14 TCR–transgenic bone marrow stem cells, followed by reconstitution, led to the expression of GSK-3βA9 in bone marrow chimeric mice. T cells from chimeric mice demonstrate a reduction in proliferation and interleukin (IL)-2 production. In contrast, in vitro assays done in the presence of the GSK-3 inhibitor lithium led to dramatically prolonged T cell proliferation and increased IL-2 production. Furthermore, in the presence of lithium, we show that nuclear factor of activated T cells (NF-AT)c remains in the nucleus after antigen-specific stimulation of T cells. Together, these data demonstrate that GSK-3 negatively regulates the duration of T cell responses.
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3 July 2000
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July 03 2000
Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase Gsk-3
Toshiaki Ohteki,
Toshiaki Ohteki
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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Michael Parsons,
Michael Parsons
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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Arsen Zakarian,
Arsen Zakarian
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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Russell G. Jones,
Russell G. Jones
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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Linh T. Nguyen,
Linh T. Nguyen
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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James R. Woodgett,
James R. Woodgett
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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Pamela S. Ohashi
Pamela S. Ohashi
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
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Toshiaki Ohteki
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
Michael Parsons
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
Arsen Zakarian
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
Russell G. Jones
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
Linh T. Nguyen
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
James R. Woodgett
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
Pamela S. Ohashi
aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada
Abbreviations used in this paper: gp, glycoprotein peptide; GSK, glycogen synthase kinase; LCMV, lymphocytic choriomeningitis virus; MSCV, murine stem cell virus; NF-AT, nuclear factor of activated T cells; RAG, recombinase-activating gene.
Received:
December 15 1999
Revision Requested:
March 03 2000
Accepted:
April 10 2000
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Exp Med (2000) 192 (1): 99–104.
Article history
Received:
December 15 1999
Revision Requested:
March 03 2000
Accepted:
April 10 2000
Citation
Toshiaki Ohteki, Michael Parsons, Arsen Zakarian, Russell G. Jones, Linh T. Nguyen, James R. Woodgett, Pamela S. Ohashi; Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase Gsk-3. J Exp Med 3 July 2000; 192 (1): 99–104. doi: https://doi.org/10.1084/jem.192.1.99
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