@article{055fa8d995cc46ab9241a68e127e1d6f,
title = "Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency",
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.",
author = "Lucas, {Carrie L.} and Kuehn, {Hye Sun} and Fang Zhao and Niemela, {Julie E.} and Deenick, {Elissa K.} and Umaimainthan Palendira and Avery, {Danielle T.} and Leen Moens and Cannons, {Jennifer L.} and Matthew Biancalana and Jennifer Stoddard and Weiming Ouyang and Frucht, {David M.} and Rao, {V. Koneti} and Atkinson, {T. Prescott} and Anahita Agharahimi and Hussey, {Ashleigh A.} and Folio, {Les R.} and Olivier, {Kenneth N.} and Fleisher, {Thomas A.} and Stefania Pittaluga and Holland, {Steven M.} and Cohen, {Jeffrey I.} and Oliveira, {Joao B.} and Tangye, {Stuart G.} and Schwartzberg, {Pamela L.} and Lenardo, {Michael J.} and Gulbu Uzel",
note = "Funding Information: 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.",
year = "2014",
month = jan,
doi = "10.1038/ni.2771",
language = "English",
volume = "15",
pages = "88--97",
journal = "Nature immunology",
issn = "1529-2908",
number = "1",
}