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

Abstract

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a key role in fundamental aspects of cell biology including survival, metabolism, proliferation and differentiation. Thus, balanced PI3K signalling is critical for multiple aspects of human health. The initial discovery that germline variants in genes in the PI3K pathway resulted in inborn errors of immunity highlighted the non-redundant role of these signalling proteins in the human immune system. The subsequent identification and characterisation of >250 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 many immune cell processes including 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 the implications of these findings for therapy in APDS patients. Expert Opinion: Fine tuning immune signalling by modulating PI3K 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.