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PMID: 24165795 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 15 ·No. 1 ·2014-01-00 ·Pages 88-97

Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G

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.

MeSH Terms
Antibiotics, Antineoplastic/therapeutic use Cell Differentiation/genetics Cells, Cultured Cellular Senescence/genetics Class I Phosphatidylinositol 3-Kinases Cytomegalovirus Infections/blood,genetics,virology Epstein-Barr Virus Infections/blood,genetics,virology Female Genes, Dominant Germ-Line Mutation Humans Immunoblotting Immunologic Deficiency Syndromes/drug therapy,genetics Male Pedigree Phosphatidylinositol 3-Kinases/chemistry,genetics Phosphorylation Proto-Oncogene Proteins c-akt/metabolism Sirolimus/therapeutic use T-Lymphocytes/metabolism TOR Serine-Threonine Kinases/metabolism Viremia/drug therapy,genetics,virology
Chemicals
Antibiotics, Antineoplastic MTOR protein, human Class I Phosphatidylinositol 3-Kinases PIK3CD protein, human Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases Sirolimus
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Lucas Carrie L
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].
Kuehn Hye Sun
1] Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. [2].
Zhao Fang
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].
Niemela Julie E
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Deenick Elissa K
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.
Palendira Umaimainthan
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.
Avery Danielle T
Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.
Moens Leen
Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.
Cannons Jennifer L
Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Biancalana Matthew
Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Stoddard Jennifer
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Ouyang Weiming
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.
Frucht David M
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.
Rao V Koneti
Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Atkinson T Prescott
Division of Allergy and Immunology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Agharahimi Anahita
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.
Hussey Ashleigh A
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Folio Les R
Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Olivier Kenneth N
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Fleisher Thomas A
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Pittaluga Stefania
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Holland Steven M
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Cohen Jeffrey I
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Oliveira Joao B
Instituto de Medicina Integral Prof. Fernando Figueira, Recife-Pernambuco, Brazil.
Tangye Stuart G
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.
Schwartzberg Pamela L
Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Lenardo Michael J
Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Uzel Gulbu
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2771
Published
2014-01-00
Epub
2013-00-28
Pages
88-97
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC4209962
Subset
IM
Grants
Intramural NIH HHS · ZIA AI000769-14 · United States
NCI NIH HHS · HHSN261200800001E · United States
Corrections
CommentIn
PMID: 24583713
External Links
PubMed source DOI: 10.1038/ni.2771 PMC Full Text View journal details
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