AUTHOR=Thauland Timothy J. , Pellerin Laurence , Ohgami Robert S. , Bacchetta Rosa , Butte Manish J. 

TITLE=Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00753

DOI=10.3389/fimmu.2019.00753

ISSN=1664-3224

ABSTRACT=<p>Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4<sup>+</sup> T cells to a T follicular helper (T<sub>FH</sub>) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote T<sub>FH</sub> differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that T<sub>FH</sub> should be monitored in APDS patients.</p>