Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells

Julia Bier, Geetha Rao, Kathryn Payne, Henry Brigden, Elise French, Simon J. Pelham, Anthony Lau, Helen Lenthall, Emily S.J. Edwards, Joanne M. Smart, Theresa S. Cole, Sharon Choo, Avni Y. Joshi, Roshini S. Abraham, Michael O'Sullivan, Kaan Boztug, Isabelle Meyts, Paul E. Gray, Lucinda J. Berglund, Peter HsuMelanie Wong, Steven M. Holland, Luigi D. Notarangelo, Gulbu Uzel, Cindy S. Ma, Robert Brink, Stuart G. Tangye, Elissa K. Deenick

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Background: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8 + T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4 + T cells in disease pathogenesis. Objective: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4 + T-cell function. Methods: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients’ CD4 + T cells and a novel murine disease model caused by overactive PI3K signaling. Results: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (T FH ) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human T FH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a T FH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4 + T cells also acquired an aberrant T FH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and T FH cells was largely CD4 + T-cell extrinsic, whereas changes in cytokine production and T FH cell function were cell intrinsic. Conclusion: Our studies reveal that CD4 + T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.

Original languageEnglish
Pages (from-to)236-253
Number of pages18
JournalJournal of Allergy and Clinical Immunology
Volume144
Issue number1
DOIs
Publication statusPublished - 1 Jul 2019
Externally publishedYes

Keywords

  • activated PI3Kδ syndrome
  • CD4 T-cell function
  • follicular helper T cells
  • humans
  • humoral immunity
  • immune class regulation
  • mouse models
  • Phosphoinositide 3-kinase
  • PIK3CD

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