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Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency


The p110delta 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 p110delta). 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.

Type Journal
ISBN 1529-2916 (Electronic) 1529-2908 (Linking)
Authors Lucas, C. L.; Kuehn, H. S.; Zhao, F.; Niemela, J. E.; Deenick, E. K.; Palendira, U.; Avery, D. T.; Moens, L.; Cannons, J. L.; Biancalana, M.; Stoddard, J.; Ouyang, W.; Frucht, D. M.; Rao, V. K.; Atkinson, T. P.; Agharahimi, A.; Hussey, A. A.; Folio, L. R.; Olivier, K. N.; Fleisher, T. A.; Pittaluga, S.; Holland, S. M.; Cohen, J. I.; Oliveira, J. B.; Tangye, S. G.; Schwartzberg, P. L.; Lenardo, M. J.; Uzel, G.;
Published Date 2014-01-01
Published Volume 15
Published Issue 1
Published Pages 88-97
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version