PI3Kδ and primary immunodeficiencies

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110 delta) and PIK3R1 (which encodes p85 alpha) that cause a combined immunodeficiency syndrome, referred to as activated PI3K delta syndrome (APDS; also known as p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3K delta in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3K delta gleaned from these patients, as well as implications of these findings for clinical therapy.