Journal
NATURE IMMUNOLOGY
Volume 15, Issue 1, Pages 88-97Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2771
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Funding
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Clinical Center of the US National Institutes of Health
- National Human Genome Research Institute of the US National Institutes of Health
- Frederick National Laboratory for Cancer Research of the US National Institutes of Health [HHSN261200800001E]
- National Health and Medical Research Council of Australia
- Cancer Council NSW
- Cancer Institute NSW
- Research Foundation-Flanders, Belgium
- National Institute of General Medical Sciences
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006201] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIAHG000123] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000646, ZIAAI000913, ZIAAI000769, ZIAAI000717, ZIAAI000732, ZIAAI000647] Funding Source: NIH RePORTER
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The p110 delta 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 p110 delta). 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.
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