title: 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 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.
authors.affiliation: 1] Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2].
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Lucas
authors.affiliation: 1] Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. [2].
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kuehn
authors.affiliation: 1] Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, USA. [3].
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.affiliation: 1] Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia. [2] St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.affiliation: 1] Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia. [2] St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Umaimainthan
authors.initials: U
authors.lastname: Palendira
authors.affiliation: Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.affiliation: Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Leen
authors.initials: L
authors.lastname: Moens
authors.affiliation: Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cannons
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Biancalana
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stoddard
authors.affiliation: Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: T Prescott
authors.initials: TP
authors.lastname: Atkinson
authors.affiliation: 1] Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] Laboratory of Clinical Infectious Diseases, Clinical Research Directorate-Clinical Monitoring Research Program, Science Applications International Corporation-Frederick, Frederick National Laboratory for Clinical Research, Frederick, Maryland, USA.
authors.forename: Anahita
authors.initials: A
authors.lastname: Agharahimi
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ashleigh A
authors.initials: AA
authors.lastname: Hussey
authors.affiliation: Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Les R
authors.initials: LR
authors.lastname: Folio
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Cohen
authors.affiliation: Instituto de Medicina Integral Prof. Fernando Figueira, Recife-Pernambuco, Brazil.
authors.forename: Joao B
authors.initials: JB
authors.lastname: Oliveira
authors.affiliation: 1] Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia. [2] St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D003586:Cytomegalovirus Infections / Q000097:blood / Q000235:genetics / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000097:blood / Q000235:genetics / Q000821:virology; D005260:Female; D005799:Genes, Dominant; D018095:Germ-Line Mutation; D006801:Humans; D015151:Immunoblotting; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D010375:Pedigree; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014766:Viremia / Q000188:drug therapy / Q000235:genetics / Q000821:virology
chemical_list: D000903:Antibiotics, Antineoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C486018:PIK3CD protein, human