Unrestrained glycogen synthase kinase-3β activity leads to activated T cell death and can be inhibited by natural adjuvant

Activated T cell death (ATCD) after peak clonal expansion is required for effective homeostasis of the immune system. Using a mouse model of T cell clonal expansion and contraction, we found that regulation of the proapoptotic kinase glycogen synthase kinase (GSK)-3 beta plays a decisive role in determining the extent to which T cells are eliminated after activation. Involvement of GSK-3 beta in ATCD was tested by measuring T cell survival after GSK-3 beta inhibition, either ex vivo with chemical and pharmacological inhibitors or in vivo by retroviral expression of a dominant-negative form of GSK-3. We also measured amounts of inactivating phosphorylation of GSK-3 beta (Ser) in T cells primed in the presence or absence of LPS. Our results show that GSK-3 beta activity is required for ATCD and that its inhibition promoted T cell survival. Adjuvant treatment in vivo maintained GSK-3 beta (Ser(9)) phosphorylation in activated T cells, whereas with adjuvant-free stimulation it peaked and then decayed as the cells became susceptible to ATCD. We conclude that the duration of GSK-3 beta inactivation determines activated T cell survival and that natural adjuvant stimulation decreases the severity of clonal contraction in part by keeping a critical proapoptotic regulatory factor, GSK-3 beta, inactivated. The Journal of Immunology, 2007, 178: 6083-6091.