Original Article

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

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/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-2D^b), we demonstrated that GSK-3ß 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-3ß that has an alanine substitution at the regulatory amino acid, serine 9 (GSK-3ßA9). Retroviral transduction of P14 TCR–transgenic bone marrow stem cells, followed by reconstitution, led to the expression of GSK-3ßA9 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.

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

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