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. 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: s.tangye@garvan.org.au. 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: e.deenick@garvan.org.au.
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 (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH 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 TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH 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.
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 (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF humanTFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH 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 TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH 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.
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