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 Hsu & 8 others Melanie 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

3 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

Cite this

Bier, Julia ; Rao, Geetha ; Payne, Kathryn ; Brigden, Henry ; French, Elise ; Pelham, Simon J. ; Lau, Anthony ; Lenthall, Helen ; Edwards, Emily S.J. ; Smart, Joanne M. ; Cole, Theresa S. ; Choo, Sharon ; Joshi, Avni Y. ; Abraham, Roshini S. ; O'Sullivan, Michael ; Boztug, Kaan ; Meyts, Isabelle ; Gray, Paul E. ; Berglund, Lucinda J. ; Hsu, Peter ; Wong, Melanie ; Holland, Steven M. ; Notarangelo, Luigi D. ; Uzel, Gulbu ; Ma, Cindy S. ; Brink, Robert ; Tangye, Stuart G. ; Deenick, Elissa K. / Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells. In: Journal of Allergy and Clinical Immunology. 2019 ; Vol. 144, No. 1. pp. 236-253.
@article{4fb5ca54674746b1b3439e197f4cc4d8,
title = "Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells",
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.",
keywords = "activated PI3Kδ syndrome, CD4 T-cell function, follicular helper T cells, humans, humoral immunity, immune class regulation, mouse models, Phosphoinositide 3-kinase, PIK3CD",
author = "Julia Bier and Geetha Rao and Kathryn Payne and Henry Brigden and Elise French and Pelham, {Simon J.} and Anthony Lau and Helen Lenthall and Edwards, {Emily S.J.} and Smart, {Joanne M.} and Cole, {Theresa S.} and Sharon Choo and Joshi, {Avni Y.} and Abraham, {Roshini S.} and Michael O'Sullivan and Kaan Boztug and Isabelle Meyts and Gray, {Paul E.} and Berglund, {Lucinda J.} and Peter Hsu and Melanie Wong and Holland, {Steven M.} and Notarangelo, {Luigi D.} and Gulbu Uzel and Ma, {Cindy S.} and Robert Brink and Tangye, {Stuart G.} and Deenick, {Elissa K.}",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/j.jaci.2019.01.033",
language = "English",
volume = "144",
pages = "236--253",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Elsevier",
number = "1",

}

Bier, J, Rao, G, Payne, K, Brigden, H, French, E, Pelham, SJ, Lau, A, Lenthall, H, Edwards, ESJ, Smart, JM, Cole, TS, Choo, S, Joshi, AY, Abraham, RS, O'Sullivan, M, Boztug, K, Meyts, I, Gray, PE, Berglund, LJ, Hsu, P, Wong, M, Holland, SM, Notarangelo, LD, Uzel, G, Ma, CS, Brink, R, Tangye, SG & Deenick, EK 2019, 'Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells', Journal of Allergy and Clinical Immunology, vol. 144, no. 1, pp. 236-253. https://doi.org/10.1016/j.jaci.2019.01.033

Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells. / Bier, Julia; Rao, Geetha; Payne, Kathryn; Brigden, Henry; French, Elise; Pelham, Simon J.; Lau, Anthony; Lenthall, Helen; Edwards, Emily S.J.; Smart, Joanne M.; Cole, Theresa S.; Choo, Sharon; Joshi, Avni Y.; Abraham, Roshini S.; O'Sullivan, Michael; Boztug, Kaan; Meyts, Isabelle; Gray, Paul E.; Berglund, Lucinda J.; Hsu, Peter; Wong, Melanie; Holland, Steven M.; Notarangelo, Luigi D.; Uzel, Gulbu; Ma, Cindy S.; Brink, Robert; Tangye, Stuart G.; Deenick, Elissa K.

In: Journal of Allergy and Clinical Immunology, Vol. 144, No. 1, 01.07.2019, p. 236-253.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells

AU - Bier, Julia

AU - Rao, Geetha

AU - Payne, Kathryn

AU - Brigden, Henry

AU - French, Elise

AU - Pelham, Simon J.

AU - Lau, Anthony

AU - Lenthall, Helen

AU - Edwards, Emily S.J.

AU - Smart, Joanne M.

AU - Cole, Theresa S.

AU - Choo, Sharon

AU - Joshi, Avni Y.

AU - Abraham, Roshini S.

AU - O'Sullivan, Michael

AU - Boztug, Kaan

AU - Meyts, Isabelle

AU - Gray, Paul E.

AU - Berglund, Lucinda J.

AU - Hsu, Peter

AU - Wong, Melanie

AU - Holland, Steven M.

AU - Notarangelo, Luigi D.

AU - Uzel, Gulbu

AU - Ma, Cindy S.

AU - Brink, Robert

AU - Tangye, Stuart G.

AU - Deenick, Elissa K.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - activated PI3Kδ syndrome

KW - CD4 T-cell function

KW - follicular helper T cells

KW - humans

KW - humoral immunity

KW - immune class regulation

KW - mouse models

KW - Phosphoinositide 3-kinase

KW - PIK3CD

UR - http://www.scopus.com/inward/record.url?scp=85062395909&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2019.01.033

DO - 10.1016/j.jaci.2019.01.033

M3 - Article

VL - 144

SP - 236

EP - 253

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 1

ER -