Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency

Abstract

The p110δ subunit of phosphoinositide 3-kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report three different germline, heterozygous, gain-of-function mutations in the PIK3CD gene encoding p110δ in fourteen patients from seven families. These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and CMV and/or EBV viremia. Strikingly, naïve and central memory T cells were severely deficient, while senescent effector T cells were over-represented. In vitro, patient T cells exhibited increased phosphorylation of Akt and hyperactivation of mTOR, enhanced glucose uptake and terminal effector differentiation. Importantly, treatment with rapamycin to inhibit mTOR activity in vivo partially restored naïve T cells, largely rescued the in vitro T cell defects, and improved clinical course.

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

“…[15][16][17] In fact, some patients identified with PIK3C have already been demonstrated to respond to sirolimus in a pilot trial. 16 Although we are unable to test our patients for these newly described mutations, their identification support additional rationale for the use of sirolimus, and may help identify those patients more likely to respond based on disease biology.…”

Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

“…Immunological findings described previously in APDS include B cell lymphopenia with relatively increased transitional B cell numbers and reduced immunoglobulin (Ig)G, but elevated IgM levels in serum [6,7], features that are shared partially with CVID [10]. The differential diagnosis of APDS also extends to combined immunodeficiency (CID) or 'atypical' severe combined immunodeficiency (SCID) (defined as immunodeficiency due to mutations in SCID-causing genes in patients with a presentation different from typical SCID and Omenn syndrome and T cell levels above 500 cells/ll [11,12]).…”

“…In APDS, increased Akt/mTOR signalling leads to an immune dysregulation and an immunodeficiency, characterized by respiratory infections, bronchiectasis and autoimmune cytopenias [6,7]. Loss of function mutations in phosphatidylinositol 3-kinase regulatory (PIK3R1) encoding the p85a regulatory subunit also result in hyperactivation of PI3K signalling with the same phenotype resulting from PIK3CD gain of function mutations, namely immunodeficiency, lymphoproliferation, poor antibody responses and expansion of senescent CD8…”

“…Correspondingly, patients with activating mutations of PI3Kd have been described to exhibit benign and malignant lymphoproliferative disease, often in association with EBV viraemia [7]. Among eight APDS patients reported by Kracker and co-authors, two developed B cell lymphoma [18].…”

Impaired caudal fin‐fold regeneration in zebrafish deficient for the tumor suppressor Pten

“…Oncogenes expressed in normal healthy cells induce senescence (Gorgoulis & Halazonetis, 2010), and hyper‐active AKT has been shown to do the same in mouse embryonic and human fibroblasts (Astle et al., 2012; Chen et al., 2005). Moreover, T‐cell senescence occurs in some immunodeficient patients with germline gain‐of‐function mutations in PI3K (Lucas et al., 2014). Therefore, elevated p‐AKT in our ptena −/− ptenb −/− embryos (Figs.…”