Phosphatidylinositol 3-kinase signaling and immune regulation: insights into disease pathogenesis and clinical implications.

INTRODUCTION: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a fundamental role in cell survival, metabolism, proliferation and differentiation. Thus, balanced PI3K signalling is critical for multiple aspects of human health. The discovery that germline variants in genes in the PI3K pathway caused inborn errors of immunity highlighted the non-redundant role of these signalling proteins in the human immune system. The subsequent identification and characterisation of >300 individuals with a novel immune dysregulatory disorder, termed activated PI3K-delta syndrome (APDS), has reinforced the status of PI3K as a key pathway regulating immune function. Studies of APDS have demonstrated that dysregulated PI3K function is disruptive for immune cell development, activation, differentiation, effector function and self-tolerance, which are all important in supporting effective, long-term immune responses. AREAS COVERED: In this review, we recount recent findings regarding humans with germline variants in PI3K genes and discuss the underlying cellular and molecular pathologies, with a focus on implications for therapy in APDS patients. EXPERT OPINION: Modulating PI3K immune cell signalling by offers opportunities for therapeutic interventions in settings of immunodeficiency, autoimmunity and malignancy, but also highlights potential adverse events that may result from overt pharmacological or intrinsic inhibition of PI3K function.