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.

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GenBank/EMBL/DDBJ

Protein Data Bank

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Acknowledgements

We thank the referring physicians, as well as the patients and families. Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Clinical Center of the US National Institutes of Health (C.L.L., H.S.K., J.E.N., M.B., J.S., W.O., V.K.R., A.A., A.A.H., K.N.O., T.A.F., S.P., S.M.H., J.I.C., M.J.L., G.U.), the National Human Genome Research Institute of the US National Institutes of Health (F.Z., J.L.C., P.L.S.), the Frederick National Laboratory for Cancer Research of the US National Institutes of Health (HHSN261200800001E), the National Health and Medical Research Council of Australia (E.K.D., U.P., S.G.T.), Cancer Council NSW (S.G.T.), the Cancer Institute NSW (U.P.), the Research Foundation-Flanders, Belgium (L.M.) and the National Institute of General Medical Sciences (C.L.L. and R.Z.). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Author information

Author notes

    • Carrie L Lucas
    • , Hye Sun Kuehn
    •  & Fang Zhao

    These authors contributed equally to this work.

Affiliations

  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.

    • Carrie L Lucas
    • , Matthew Biancalana
    • , V Koneti Rao
    •  & Michael J Lenardo
  2. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

    • Hye Sun Kuehn
    • , Julie E Niemela
    • , Jennifer Stoddard
    •  & Thomas A Fleisher
  3. Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Fang Zhao
    • , Jennifer L Cannons
    •  & Pamela L Schwartzberg
  4. Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, USA.

    • Fang Zhao
  5. Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.

    • Elissa K Deenick
    • , Umaimainthan Palendira
    • , Danielle T Avery
    • , Leen Moens
    •  & Stuart G Tangye
  6. St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, Australia.

    • Elissa K Deenick
    • , Umaimainthan Palendira
    •  & Stuart G Tangye
  7. 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.

    • Weiming Ouyang
    •  & David M Frucht
  8. Division of Allergy and Immunology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • T Prescott Atkinson
  9. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Anahita Agharahimi
    • , Ashleigh A Hussey
    • , Kenneth N Olivier
    • , Steven M Holland
    •  & Gulbu Uzel
  10. 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.

    • Anahita Agharahimi
  11. Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

    • Les R Folio
  12. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Stefania Pittaluga
  13. Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Jeffrey I Cohen
  14. Instituto de Medicina Integral Prof. Fernando Figueira, Recife-Pernambuco, Brazil.

    • Joao B Oliveira

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Contributions

C.L.L did experiments, analyzed data and developed and wrote the manuscript; H.S.K., F.Z., E.K.D., U.P., D.T.A., L.M. and J.L.C. did experiments and analyzed data; J.E.N. analyzed genomic DNA sequencing and bioinformatics, discovered candidate genes and analyzed protein structure; M.B. analyzed p110 structure; J.S. did experiments and analyzed genomic DNA sequencing and data; W.O. did experiments; D.M.F. supervised research and data analysis; V.K.R. evaluated patients and collected data; T.P.A. and J.I.C. provided patient access, clinical data, samples and advice; A.A. evaluated patients and collected and analyzed data; A.A.H. coordinated patient access, data collection and analysis; L.R.F. evaluated and prepared data from clinical imaging studies; K.N.O. evaluated patients and collected and analyzed data; T.A.F. supervised research and data analysis and provided advice; S.P. did histological and immunohistochemical analyses of patient samples; S.M.H. supervised research and data analysis and provided advice; J.B.O planned and supervised whole-exome sequencing experiments; S.G.T. planned and supervised experiments, analyzed data, provided advice and prepared the manuscript; P.L.S. planned and supervised experiments, analyzed data and provided advice; M.J.L. supervised research and data analysis, provided advice and prepared the manuscript; G.U. coordinated research efforts, supervised research work and data analysis, and prepared the manuscript; and all authors discussed and revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gulbu Uzel.

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DOI

https://doi.org/10.1038/ni.2771

Note added in proof: Another study has now independently described a cohort of patients with the E1021K substitution of p110δ48.

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