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

Front Immunol. 2019 Apr 12:10:753. doi: 10.3389/fimmu.2019.00753. eCollection 2019.

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.

Keywords: PI3K; T follicular helper cells; activated PI3K delta syndrome (APDS); osteopontin; primary immunodeficiency.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Amino Acid Substitution
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD4 Lymphocyte Count
  • Child
  • Class I Phosphatidylinositol 3-Kinases / chemistry
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Female
  • Humans
  • Immunophenotyping
  • Models, Biological
  • Models, Molecular
  • Mutation
  • Pedigree
  • Primary Immunodeficiency Diseases / diagnosis*
  • Primary Immunodeficiency Diseases / etiology*
  • Protein Conformation
  • Structure-Activity Relationship
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism*

Substances

  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human

Supplementary concepts

  • Activated PI3K-delta Syndrome