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

Carrie L Lucas; Hye Sun Kuehn; Fang Zhao; Julie E Niemela; Elissa K Deenick; Umaimainthan Palendira; Danielle T Avery; Leen Moens; Jennifer L Cannons; Matthew Biancalana; Jennifer Stoddard; Weiming Ouyang; David M Frucht; V Koneti Rao; T Prescott Atkinson; Anahita Agharahimi; Ashleigh A Hussey; Les R Folio; Kenneth N Olivier; Thomas A Fleisher; Stefania Pittaluga; Steven M Holland; Jeffrey I Cohen; Joao B Oliveira; Stuart G Tangye; Pamela L Schwartzberg; Michael J Lenardo; Gulbu Uzel

doi:10.1038/ni.2771

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

Nat Immunol. 2014 Jan;15(1):88-97. doi: 10.1038/ni.2771. Epub 2013 Oct 28.

Authors

Carrie L Lucas¹, Hye Sun Kuehn², Fang Zhao³, Julie E Niemela⁴, Elissa K Deenick⁵, Umaimainthan Palendira⁵, Danielle T Avery⁶, Leen Moens⁶, Jennifer L Cannons⁷, Matthew Biancalana⁸, Jennifer Stoddard⁴, Weiming Ouyang⁹, David M Frucht⁹, V Koneti Rao⁸, T Prescott Atkinson¹⁰, Anahita Agharahimi¹¹, Ashleigh A Hussey¹², Les R Folio¹³, Kenneth N Olivier¹², Thomas A Fleisher⁴, Stefania Pittaluga¹⁴, Steven M Holland¹², Jeffrey I Cohen¹⁵, Joao B Oliveira¹⁶, Stuart G Tangye⁵, Pamela L Schwartzberg⁷, Michael J Lenardo⁸, Gulbu Uzel¹²

Affiliations

¹ 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].
² 1] Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. [2].
³ 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].
⁴ Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
⁵ 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.
⁶ Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.
⁷ Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁸ Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁹ 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.
¹⁰ Division of Allergy and Immunology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹¹ 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.
¹² Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹³ Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
¹⁴ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁵ Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹⁶ Instituto de Medicina Integral Prof. Fernando Figueira, Recife-Pernambuco, Brazil.

PMID: 24165795
PMCID: PMC4209962
DOI: 10.1038/ni.2771

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibiotics, Antineoplastic / therapeutic use
Cell Differentiation / genetics
Cells, Cultured
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
Genes, Dominant
Germ-Line Mutation*
Humans
Immunoblotting
Immunologic Deficiency Syndromes / drug therapy
Immunologic Deficiency Syndromes / genetics*
Male
Pedigree
Phosphatidylinositol 3-Kinases / chemistry
Phosphatidylinositol 3-Kinases / genetics*
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism
Sirolimus / therapeutic use
T-Lymphocytes / metabolism*
TOR Serine-Threonine Kinases / metabolism
Viremia / drug therapy
Viremia / genetics
Viremia / virology

Substances

Antibiotics, Antineoplastic
MTOR protein, human
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Sirolimus

Abstract

Publication types

MeSH terms

Substances

Grants and funding