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Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
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Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
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Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
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Journal Article
Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
2014
Overview
Lymphocyte function is regulated by phosphatidylinositol-dependent pathways. Uzel and colleagues identify a cohort of immunodeficient patients with hyperactive phosphatidylinositol-3-OH kinase activity due to mutant p110δ subunits, which results in enhanced senescence of cells of the immune system.
The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in
PIK3CD
(which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells.
In vitro
, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity
in vivo
partially restored the abundance of naive T cells, largely 'rescued' the
in vitro
T cell defects and improved the clinical course.
Publisher
Nature Publishing Group US
Subject
/ Antibiotics, Antineoplastic - therapeutic use
/ Cell Differentiation - genetics
/ Cellular Senescence - genetics
/ Class I Phosphatidylinositol 3-Kinases
/ Cytomegalovirus Infections - blood
/ Cytomegalovirus Infections - genetics
/ Cytomegalovirus Infections - virology
/ Epstein-Barr Virus Infections - blood
/ Epstein-Barr Virus Infections - genetics
/ Epstein-Barr Virus Infections - virology
/ Female
/ Humans
/ Immunologic Deficiency Syndromes - drug therapy
/ Immunologic Deficiency Syndromes - genetics
/ Male
/ Pedigree
/ Phosphatidylinositol 3-Kinases - chemistry
/ Phosphatidylinositol 3-Kinases - genetics
/ Proto-Oncogene Proteins c-akt - metabolism
