PI3Kδ and primary immunodeficiencies

Key Points PI3Kδ (phosphoinositide 3-kinase-δ) is a key signal transduction node in cells of the immune system. This kinase complex is acutely activated in B cells and T cells after exposure to antigen and controls many aspects of lymphocyte development and differentiation, in part via the AKT, forkhead box O1 (FOXO1) and mechanistic target of rapamycin (mTOR) pathways. Rare loss-of-function mutations affecting PI3Kδ also cause immunodeficiency and immune-mediated pathologies, including colitis. The PI3Kδ inhibitor idelalisib frequently causes colitis at doses tested in leukaemia and lymphoma trials, possibly due to effects on regulatory T (T reg ) cells. Activated PI3Kδ syndrome (APDS; also called PASLI disease) is a newly described primary immunodeficiency caused by hyperactive PI3Kδ signalling and resultant T cell senescence and/or death and impaired antibody responses. APDS is generally characterized by recurrent sinopulmonary infections with structural lung damage, viraemia with herpes family viruses, lymphoproliferative disease and increased risk of B cell malignancies. Patients with APDS1 have a heterozygous mutation in PIK3CD , the gene encoding the p110δ catalytic subunit of PI3Kδ, whereas APDS2 patients have a heterozygous mutation in PIK3R1 , the gene encoding the p85α regulatory subunit of PI3Kδ. Both sets of mutations lead to higher intrinsic activity of PI3Kδ. To date, most patients with APDS have been treated with antibody replacement therapies and some have also been treated with the mTOR inhibitor rapamycin. In the future, PI3Kδ inhibitors may be used to treat these patients, possibly as the first example of targeted therapy against a hyperactive mutant kinase in primary immunodeficiency. Gain- and loss-of-function mutations in phosphoinositide 3-kinase-δ (PI3Kδ) result in a primary immunodeficiency syndrome termed APDS. Understanding the function of PI3Kδ in adaptive immune responses — from studies of mouse models of these mutations and from patients with APDS — provides new insights on how mutations in PI3Kδ promote 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 p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activa