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; Melanie Wong; Steven M Holland; Luigi D Notarangelo; Gulbu Uzel; Cindy S Ma; Robert Brink; Stuart G Tangye; Elissa K Deenick

doi:10.1016/j.jaci.2019.01.033

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

J Allergy Clin Immunol. 2019 Jul;144(1):236-253. doi: 10.1016/j.jaci.2019.01.033. Epub 2019 Feb 6.

Authors

Julia Bier¹, Geetha Rao², Kathryn Payne², Henry Brigden³, Elise French³, Simon J Pelham¹, Anthony Lau¹, Helen Lenthall², Emily S J Edwards¹, Joanne M Smart⁴, Theresa S Cole⁴, Sharon Choo⁴, Avni Y Joshi⁵, Roshini S Abraham⁶, Michael O'Sullivan⁷, Kaan Boztug⁸, Isabelle Meyts⁹, Paul E Gray¹⁰, Lucinda J Berglund¹¹, Peter Hsu¹², Melanie Wong¹², Steven M Holland¹³, Luigi D Notarangelo¹³, Gulbu Uzel¹³, Cindy S Ma¹⁴, Robert Brink¹⁴, Stuart G Tangye¹⁵, Elissa K Deenick¹⁶

Affiliations

¹ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
² Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
³ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; University of Bath, Bath, United Kingdom.
⁴ Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Melbourne, Australia.
⁵ Division of Allergy and Immunology, Mayo Clinic Children's Center, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn.
⁶ Division of Allergy and Immunology, Mayo Clinic Children's Center, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn; Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
⁷ Department of Immunology and Allergy, Princess Margaret Hospital, Subiaco, Australia.
⁸ Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; St Anna Children's Hospital and Children's Cancer Research Institute, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
⁹ Department of Immunology and Microbiology, Childhood Immunology, Department of Pediatrics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
¹⁰ School of Women's and Children's Health, University of New South Wales, Sydney, Australia; Clinical Immunogenomics Research Consortia Australia, Sydney, Australia.
¹¹ Clinical Immunogenomics Research Consortia Australia, Sydney, Australia; Immunopathology Department, Westmead Hospital, Westmead, Australia; Faculty of Medicine, University of Sydney, Sydney, Australia.
¹² Clinical Immunogenomics Research Consortia Australia, Sydney, Australia; Faculty of Medicine, University of Sydney, Sydney, Australia; Children's Hospital at Westmead, Westmead, Australia.
¹³ Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹⁴ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Clinical Immunogenomics Research Consortia Australia, Sydney, Australia.
¹⁵ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Clinical Immunogenomics Research Consortia Australia, Sydney, Australia. Electronic address: [email protected].
¹⁶ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Clinical Immunogenomics Research Consortia Australia, Sydney, Australia. Electronic address: [email protected].

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: CD4(+) T-cell function; PIK3CD; Phosphoinositide 3-kinase; activated PI3Kδ syndrome; follicular helper T cells; humans; humoral immunity; immune class regulation; mouse models.

Publication types

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

MeSH terms

Animals
CD4-Positive T-Lymphocytes* / metabolism
Cell Differentiation*
Cytokines / metabolism
Gain of Function Mutation
Humans
Mice
Phenotype
Phosphatidylinositol 3-Kinases / genetics*

Substances

Cytokines

Grants and funding

Z99 AI999999/ImNIH/Intramural NIH HHS/United States