T-lymphocyte (CTL) survival and function is critically dependent on phosphoinositide (PI) 3 kinase signaling. PI3 kinase signaling includes the PKB/Akt and SGK dependent phosphorylation of glycogen synthase kinase GSK3ab leading to GSK3 inhibition. Lithium, a known unspecific GSK3 inhibitor protects against experimental autoimmune encephalomyelitis. The present study explored, whether PKB/SGK-dependent GSK3 activity participates in the regulation of CTL survival and function. Experiments were performed in mutant mice in which PKB/SGK-dependent GSK3a,ß regulation was disrupted by replacement of the serine residue in the respective SGK/PKB-phosphorylation consensus sequence by alanine (gsk3^KI). The mice were compared to corresponding wild type mice (gsk3^WT). As a result, expression of surface markers in CD4 and CD8 T cells was similar in gsk3^KI and gsk3^WT CTL blasts but gsk3^KI CTL proliferate faster and are less sensitive to activation induced cell death than gsk3^WT CTL. Moreover, gsk3^KI CTL are less sensitive to apoptosis than gsk3^WT CTL following inhibition of PI3K (10 mM LY294002) or mTOR (100 nM mTOR inhibitor Ku-0063794). gsk3^KI CTL express significantly higher perforin levels than gsk3^WT. Upon stimulation with anti- CD3 2C11 (6h), gsk3^KI CTL secrete significantly more TNFa and IFNg than gsk3^WT CTLs. In conclusion PKB/Akt and SGK dependent phosphorylation of GSK3a,ß is a potent regulator of T lymphocyte survival and function.