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

Abstract

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 PI3Kδ, p110δ, 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 PI3Kδ 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 PI3Kδ 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 PI3Kδ in promoting multiple T-helper effector cell lineages. K E Y W O R D S APDS/PASLI, autoimmunity, immunodeficiency, phosphatidylinositol 3 kinase, T and B lymphocytes | 155 PREITE ET al. | AC TIVATED PI3K-DELTA SYNDROMEIn 2013-2014, three studies described immunodeficient patients with heterozygous gain-of-function autosomal-dominant mutations in PIK3CD, the gene encoding the catalytic subunit of PI3K p110δ. [3][4][5] At least 11 mutations have now been identified by whole exome sequencing, with the E1021K mutant being most prevalent. 2,6 Based on similar mutations in PI3Kα found in cancers and overgrowth syndromes, p110δ mutations were predicted to activate p110δ. 4,7 Indeed, increased PI3K activity and downstream readouts including increased PIP 3 levels, pAKT and pS6, have been observed in cells from these patients. 3,4 This novel PID has been named "Activated PI3K-delta syndrome" (APDS) or "p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI), hereafter referred to as APDS. Activated PI3K-delta syndrome is a combined immunodeficiency syndrome characterized by altered T-and B-cell development and responses. APDS is associated with frequent respiratory infections, progressive blood lymphopenia, mucosal lymphoid nodules, defective antibody responses, and lymphoma development. 2 Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B-cell development is partially blocked, with increased transitional and few circulating memory B cells. 4,8,9 Recurrent respiratory infections are the most common feature of APDS. However, Epstein-Barr virus (EBV) and/ or cytomegalovirus (CMV) viremia occurs in a substantial fraction of patients, ...

Control of T lymphocyte fate decisions by PI3K signaling

“…Mechanistically, these mutations function either by disrupting the inhibitory contacts of p110 with p85 or by increasing the affinity of p110δ for the plasma membrane, promoting its interaction with PIP 2 53 . Consistent with the known functions of PI3K signaling, APDS mutations result in enhanced activation of the Akt and mTOR kinase pathways and decreased activity of the FOXO1 transcription factor in T cells 50 . These changes are associated with increased T cell effector function and enhanced migration out of secondary lymphoid organs.…”

“…Facilitating the understanding of APDS, a mouse model of active PI3K (Pik3cd E1020K/+ ) reproduces many aspects of this disease 45 – 49 . Clinical and cellular aspects of APDS have been reviewed extensively elsewhere 50 – 52 , so we will touch on a few highlights here.…”

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

“…PI3Kδ is a PI3K subunit exclusively expressed in leukocytes. Patients heterozygous for this mutation are now said to have "activated PI3Kδ syndrome, " or APDS, of which ∼200 patients have been described to date (88). Activated PI3Kδ syndrome is characterized by impaired T-and B-cell development and function, autoimmunity, and lymphoproliferation.…”

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients

“…Clinical hallmarks of the disease are recurrent sinopulmonary infections, severe or persistent viral infections, autoimmunity (e.g., cytopenia, arthritis, enteropathy) and chronic benign lymphoproliferation with increased risk of developing lymphomas [ 8 , 9 , 10 , 11 ]. APDS-1 patients display defects in both B- and T-cells: usual findings include lymphopenia, normal to elevated serum immunoglobulin M (IgM) levels, and reduced levels of immunoglobulin G (IgG) with impaired ability to produce antibodies against vaccines [ 12 , 13 , 14 , 15 ].…”