Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase GSK-3

doi:10.1084/jem.192.1.99

Published online 3 July 2000.

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© The Rockefeller University Press, 0022-1007/2000/7/99/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 1, July 3, 2000 99-104

Original Article

Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase GSK-3

Toshiaki Ohteki^a, Michael Parsons^a, Arsen Zakarian^a, Russell G. Jones^a, Linh T. Nguyen^a, James R. Woodgett^a, and Pamela S. Ohashi^a
^a Ontario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada

Correspondence to: Pamela S. Ohashi, Ontario Cancer Institute, Dept. of Medical Biophysics, 610 University Ave., Toronto, ON M5G 2M9, Canada. Tel:416-946-4501 ext. 5470 Fax:416-946-2086 E-mail:pohashi{at}oci.utoronto.ca.

Glycogen synthase kinase (GSK)-3 is a protein serine/threoninekinase that regulates differentiation and cell fate in a varietyof organisms. This study examined the role of GSK-3 in antigen-specificT cell responses. Using resting T cells from P14 T cell receptor(TCR)-transgenic mice (specific for the lymphocytic choriomeningitisvirus and H-2D^b), we demonstrated that GSK-3ß was inactivatedby serine phosphorylation after viral peptide–specificstimulation in vitro. To further investigate the role of GSK-3,we have generated a retroviral vector that expresses a constitutivelyactive form of GSK-3ß that has an alanine substitutionat the regulatory amino acid, serine 9 (GSK-3ßA9). Retroviraltransduction of P14 TCR–transgenic bone marrow stem cells,followed by reconstitution, led to the expression of GSK-3ßA9in bone marrow chimeric mice. T cells from chimeric mice demonstratea reduction in proliferation and interleukin (IL)-2 production.In contrast, in vitro assays done in the presence of the GSK-3inhibitor lithium led to dramatically prolonged T cell proliferationand increased IL-2 production. Furthermore, in the presenceof lithium, we show that nuclear factor of activated T cells(NF-AT)c remains in the nucleus after antigen-specific stimulationof T cells. Together, these data demonstrate that GSK-3 negativelyregulates the duration of T cell responses.

Key Words: signaling, NF-AT, T cell activation, cytokines, lymphocytes

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