Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3

Glycogen synthase kinase (GSK)-3 is a protein serine/threonine kinase that regulates differentiation and cell fate in a variety of organisms. This stu dy examined the role of GSK-3 in antigen-specific T cell responses. Using r esting T cells from P14 T cell receptor (TCR)-transgenic mice (specific for the lymphocytic choriomeningitis virus and H-2D(b)), we demonstrated that GSK-3 beta was inactivated by serine phosphorylation after viral peptide-sp ecific stimulation in vitro. To further investigate the role of GSK-3, we h ave generated a retroviral vector that expresses a constitutively active fo rm of GSK-3 beta that has an alanine substitution at the regulatory amino a cid, serine 9 (GSK-3 beta A9). Retroviral transduction of P14 TCR-transgeni c hone marrow stem cells, followed by reconstitution, led to the expression of GSK-3 beta A9 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 l ithium 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 Lifter antigen -specific stimulation of T cells. Together, these data demonstrate that GSK -3 negatively regulates the duration of T cell responses.