T and B-cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3K delta, p110 delta, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder Activated PI3K-delta syndrome and mouse models of this disease (Pik3cd(E1020K/+) mice) have provided fundamental insight into pathways regulated by PI3K delta in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3K delta in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8(+) T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1(AAA) mutant to rescue IgG1 class switching defects in Pik3cd(E1020K/+) B cells, as well as data supporting a role for PI3K delta in promoting multiple T-helper effector cell lineages.