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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.



Protein Data Bank


  1. 1.

    & PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 3, 317–330 (2003).

  2. 2.

    & PI3K-PKB/Akt pathway. Cold Spring Harb. Perspect. Biol. 4, a011189 (2012).

  3. 3.

    et al. p110δ, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J. Biol. Chem. 272, 19236–19241 (1997).

  4. 4.

    et al. P110δ, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl. Acad. Sci. USA 94, 4330–4335 (1997).

  5. 5.

    et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 1744–1748 (2007).

  6. 6.

    et al. Rapid effector function of memory CD8 T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).

  7. 7.

    , , & mTOR, linking metabolism and immunity. Semin. Immunol. 24, 429–435 (2012).

  8. 8.

    & mTOR and metabolic pathways in T cell quiescence and functional activation. Semin. Immunol. 24, 421–428 (2012).

  9. 9.

    , , & Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).

  10. 10.

    et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261–269 (1997).

  11. 11.

    , , & Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

  12. 12.

    & Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).

  13. 13.

    et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).

  14. 14.

    , & Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844–852 (2005).

  15. 15.

    et al. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene 31, 1949–1962 (2012).

  16. 16.

    & Role of PI3K/Akt signaling in memory CD8 T cell differentiation. Front. Immunol. 4, 20 (2013).

  17. 17.

    et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

  18. 18.

    et al. Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J. Immunol. 188, 4305–4314 (2012).

  19. 19.

    et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013).

  20. 20.

    , & Epidemiology of EBV and Hodgkin's lymphoma. Ann. Oncol. 7 (suppl. 4), 5–10 (1996).

  21. 21.

    et al. The p110 d structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol. 6, 117–124 (2010).

  22. 22.

    , , & Oncogenic PI3K deregulates transcription and translation. Nat. Rev. Cancer 5, 921–929 (2005).

  23. 23.

    et al. A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane. Proc. Natl. Acad. Sci. USA 106, 16996–17001 (2009).

  24. 24.

    et al. Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants. Proc. Natl. Acad. Sci. USA 106, 20258–20263 (2009).

  25. 25.

    & Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA 105, 2652–2657 (2008).

  26. 26.

    et al. Identification of variations in the human phosphoinositide 3-kinase p110δ gene in children with primary B-cell immunodeficiency of unknown aetiology. Int. J. Immunogenet. 33, 361–369 (2006).

  27. 27.

    et al. Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling. EMBO Mol. Med. 5, 1278–1295 (2013).

  28. 28.

    et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011).

  29. 29.

    et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101, 2711–2720 (2003).

  30. 30.

    et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J. Biol. Chem. 282, 14056–14064 (2007).

  31. 31.

    et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031–1034 (2002).

  32. 32.

    et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α. Science 283, 393–397 (1999).

  33. 33.

    et al. Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 283, 390–392 (1999).

  34. 34.

    et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J. Exp. Med. 209, 463–470 (2012).

  35. 35.

    et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

  36. 36.

    , , & Oncogenic signaling of class I PI3K isoforms. Oncogene 27, 2561–2574 (2008).

  37. 37.

    & Class I PI3K in oncogenic cellular transformation. Oncogene 27, 5486–5496 (2008).

  38. 38.

    & The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

  39. 39.

    et al. A selective inhibitor of the p110 d isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 25, 6648–6659 (2006).

  40. 40.

    et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).

  41. 41.

    et al. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity 25, 545–557 (2006).

  42. 42.

    et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

  43. 43.

    et al. Structural comparisons of class I phosphoinositide 3-kinases. Nat. Rev. Cancer 8, 665–669 (2008).

  44. 44.

    et al. The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation. PLoS ONE 8, e70024 (2013)

  45. 45.

    , , & Generation and maintenance of immunological memory. Semin. Immunol. 16, 323–333 (2004).

  46. 46.

    , & Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov. 5, 671–688 (2006).

  47. 47.

    et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117, 591–594 (2011).

  48. 48.

    et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science (17 October 2013).

  49. 49.

    et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol. 7, 539 (2011).

  50. 50.

    et al. Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP. PLoS Biol. 9, e1001187 (2011).

  51. 51.

    et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J. Exp. Med. 207, 155–171 (2010).

Download references


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.


  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


  1. Search for Carrie L Lucas in:

  2. Search for Hye Sun Kuehn in:

  3. Search for Fang Zhao in:

  4. Search for Julie E Niemela in:

  5. Search for Elissa K Deenick in:

  6. Search for Umaimainthan Palendira in:

  7. Search for Danielle T Avery in:

  8. Search for Leen Moens in:

  9. Search for Jennifer L Cannons in:

  10. Search for Matthew Biancalana in:

  11. Search for Jennifer Stoddard in:

  12. Search for Weiming Ouyang in:

  13. Search for David M Frucht in:

  14. Search for V Koneti Rao in:

  15. Search for T Prescott Atkinson in:

  16. Search for Anahita Agharahimi in:

  17. Search for Ashleigh A Hussey in:

  18. Search for Les R Folio in:

  19. Search for Kenneth N Olivier in:

  20. Search for Thomas A Fleisher in:

  21. Search for Stefania Pittaluga in:

  22. Search for Steven M Holland in:

  23. Search for Jeffrey I Cohen in:

  24. Search for Joao B Oliveira in:

  25. Search for Stuart G Tangye in:

  26. Search for Pamela L Schwartzberg in:

  27. Search for Michael J Lenardo in:

  28. Search for Gulbu Uzel in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Figures and Supplementary Tables

    Supplementary Figures 1–9 and Supplementary Tables 1–3

About this article

Publication history






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

Further reading