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

Nat Immunol. 2014 Jan;15(1):88-97. doi: 10.1038/ni.2771. Epub 2013 Oct 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / therapeutic use
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Class I Phosphatidylinositol 3-Kinases
  • Cytomegalovirus Infections / blood
  • Cytomegalovirus Infections / genetics
  • Cytomegalovirus Infections / virology
  • Epstein-Barr Virus Infections / blood
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / virology
  • Female
  • Genes, Dominant
  • Germ-Line Mutation*
  • Humans
  • Immunoblotting
  • Immunologic Deficiency Syndromes / drug therapy
  • Immunologic Deficiency Syndromes / genetics*
  • Male
  • Pedigree
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sirolimus / therapeutic use
  • T-Lymphocytes / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Viremia / drug therapy
  • Viremia / genetics
  • Viremia / virology

Substances

  • Antibiotics, Antineoplastic
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human
  • Proto-Oncogene Proteins c-akt
  • Sirolimus