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Artigo Acesso aberto Produção Nacional Revisado por pares
BIBTEX RIS

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

2013; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/ni.2771

ISSN

1529-2916

Autores

C. 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 Folio, Kenneth N. Olivier, Thomas A. Fleisher, Stefania Pittaluga, Steven M. Holland, Jeffrey I. Cohen, João Bosco Oliveira, Stuart G. Tangye, Pamela L. Schwartzberg, Michael J. Lenardo, Gülbû Uzel,

Tópico(s)

PI3K/AKT/mTOR signaling in cancer

Resumo

Lymphocyte function is regulated by phosphatidylinositol-dependent pathways. Uzel and colleagues identify a cohort of immunodeficient patients with hyperactive phosphatidylinositol-3-OH kinase activity due to mutant p110δ subunits, which results in enhanced senescence of cells of the immune system. 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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