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

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

Author information

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.

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.

Comment in

PMID:
24165795
PMCID:
PMC4209962
DOI:
10.1038/ni.2771
[Indexed for MEDLINE]
Free PMC Article

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