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

Carrie L. Lucas, Hye Sun Kuehn, Fang Zhao, Julie E. Niemela, Elissa K. Deenick, Umaimainthan Palendira, Danielle T. Avery, Leen Moens, Jennifer L. Cannons, Matthew Biancalana, Jennifer Stoddard, Weiming Ouyang, David M. Frucht, V. Koneti Rao, T. Prescott Atkinson, Anahita Agharahimi, Ashleigh A. Hussey, Les R. Folio, Kenneth N. Olivier, Thomas A. FleisherStefania Pittaluga, Steven M. Holland, Jeffrey I. Cohen, Joao B. Oliveira, Stuart G. Tangye, Pamela L. Schwartzberg, Michael J. Lenardo, Gulbu Uzel

Research output: Contribution to journalArticlepeer-review

416 Scopus citations

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.

Original languageEnglish
Pages (from-to)88-97
Number of pages10
JournalNature immunology
Volume15
Issue number1
DOIs
StatePublished - Jan 2014

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