AKT/SGK-sensitive phosphorylation of GSK3 in the regulation of L-selectin and perforin expression as well as activation induced cell death of T-lymphocytes

Survival and function of T-lymphocytes critically depends on phosphoinositide (PI) 3 kinase. PI3 kinase signaling includes the PKB/Akt and SGK dependent phosphorylation and thus inhibition of glycogen synthase kinase GSK3α,β. Lithium, a known unspecific GSK3 inhibitor protects against experimental autoimmune encephalomyelitis. The present study explored, whether Akt/SGK-dependent regulation of GSK3 activity is a determinant of T cell survival and function. Experiments were performed in mutant mice in which Akt/SGK-dependent GSK3α,β inhibition was disrupted by replacement of the serine residue in the respective SGK/Akt-phosphorylation consensus sequence by alanine (gsk3KI). T cells from gsk3KI mice were compared to T cells from corresponding wild type mice (gsk3WT). As a result, in gsk3KI CD4+ cells surface CD62L (L-selectin) was significantly less abundant than in gsk3WT CD4+ cells. Upon activation in vitro T cells from gsk3KI mice reacted with enhanced perforin production and reduced activation induced cell death. Cytokine production was rather reduced in gsk3KI T cells, suggesting that GSK3 induces effector function in CD8+ T cells. In conclusion, PKB/Akt and SGK sensitive phosphorylation of GSK3α,β is a potent regulator of perforin expression and activation induced cell death in T lymphocytes.

► Akt/SGK dependent phosphorylation of GSK3α,β regulates T lymphocytes. ► T cells from mice expressing Akt/SGK insensitive GSK3α,β (gsk3KI) release less IL-2. ► CD4+ cells from gsk3KI mice express less CD62L. ► CD8+ cells from gsk3KI mice are relatively resistant to activation induced cell death. ► Perforin expression is enhanced in gsk3KI T cells.