Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome.
Front Immunol
; 10: 753, 2019.
Article
in En
| MEDLINE
| ID: mdl-31031754
ABSTRACT
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+ T cells to a T follicular helper (TFH) 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 TFH 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 TFH should be monitored in APDS patients.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes, Helper-Inducer
/
Class I Phosphatidylinositol 3-Kinases
/
Primary Immunodeficiency Diseases
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Child
/
Female
/
Humans
Language:
En
Journal:
Front Immunol
Year:
2019
Type:
Article
Affiliation country:
United States