Dominant-Activating, Germline Mutations in Phosphoinositide 3-Kinase p110δ Cause T Cell Senescence and Human Immunodeficiency

• Published in: Nature immunology Vol. 15; no. 1; pp. 88 - 97
• Main Authors: Lucas, Carrie L., Kuehn, Hye Sun, Zhao, Fang, Niemela, Julie E., Deenick, Elissa K., Palendira, Umaimainthan, Avery, Danielle T., Moens, Leen, Cannons, Jennifer L., Biancalana, Matthew, Stoddard, Jennifer, Ouyang, Weiming, Frucht, David L., Rao, V. Koneti, Atkinson, T. Prescott, Agharahimi, Anahita, Hussey, Ashleigh A., Folio, Les R., Olivier, Kenneth N., Fleisher, Thomas A., Pittaluga, Stefania, Holland, Steven M., Cohen, Jeffrey I., Oliviera, Joao B., Tangye, Stuart G., Schwartzberg, Pamela L., Lenardo, Michael J., Uzel, Gulbu
• Format: Journal Article
• Language: English
• Published: 28.10.2013
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2771

The p110δ subunit of phosphoinositide 3-kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report three different germline, heterozygous, gain-of-function mutations in the PIK3CD gene encoding p110δ in fourteen patients from seven families. These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and CMV and/or EBV viremia. Strikingly, naïve and central memory T cells were severely deficient, while senescent effector T cells were over-represented. In vitro , patient T cells exhibited increased phosphorylation of Akt and hyperactivation of mTOR, enhanced glucose uptake and terminal effector differentiation. Importantly, treatment with rapamycin to inhibit mTOR activity in vivo partially restored naïve T cells, largely rescued the in vitro T cell defects, and improved clinical course.