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Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4+ T cells - 07/03/19

Doi : 10.1016/j.jaci.2019.01.033 
Julia Bier, MSc a, b, Geetha Rao, MSc a, Kathryn Payne, BSc (Hons) a, Henry Brigden, BSc (Hons) a, c, Elise French, BSc (Hons) a, c, Simon J. Pelham, MSc a, b, Anthony Lau, BSc (Hons) a, b, Helen Lenthall, MMSc a, Emily S.J. Edwards, PhD a, b, , Joanne M. Smart, MBBS, FRACP d, Theresa S. Cole, BM, FRACP, PhD d, Sharon Choo, MBBS, FRACP, FRCPA d, Avni Y. Joshi, MD e, Roshini S. Abraham, PhD e, f, Michael O'Sullivan, MBBS g, Kaan Boztug, MD h, i, j, Isabelle Meyts, MD, PhD k, Paul E. Gray, FRACP l, m, Lucinda J. Berglund, MBBS, PhD m, n, o, Peter Hsu, FRACP, PhD m, o, p, Melanie Wong, MBBS, PhD m, o, p, Steven M. Holland, MD q, Luigi D. Notarangelo, MD q, Gulbu Uzel, MD q, Cindy S. Ma, PhD a, b, m, Robert Brink, PhD a, b, m, Stuart G. Tangye, PhD a, b, m, , Elissa K. Deenick, PhD a, b, m,
a Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia 
b St Vincent's Clinical School, University of New South Wales, Sydney, Australia 
c University of Bath, Bath, United Kingdom 
d Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Melbourne, Australia 
e Division of Allergy and Immunology, Mayo Clinic Children's Center, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn 
f Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 
g Department of Immunology and Allergy, Princess Margaret Hospital, Subiaco, Australia 
h Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria 
i CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria 
j St Anna Children's Hospital and Children's Cancer Research Institute, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria 
k Department of Immunology and Microbiology, Childhood Immunology, Department of Pediatrics, University Hospitals Leuven and KU Leuven, Leuven, Belgium 
l School of Women's and Children's Health, University of New South Wales, Sydney, Australia 
m Clinical Immunogenomics Research Consortia Australia, Sydney, Australia 
n Immunopathology Department, Westmead Hospital, Westmead, Australia 
o Faculty of Medicine, University of Sydney, Sydney, Australia 
p Children's Hospital at Westmead, Westmead, Australia 
q Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md 

Corresponding authors: Elissa K. Deenick, PhD, and Stuart G. Tangye, PhD, Immunology Division, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia.Immunology DivisionGarvan Institute of Medical Research384 Victoria StDarlinghurstNSW2010Australia
En prensa. Pruebas corregidas por el autor. Disponible en línea desde el Thursday 07 March 2019
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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.

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Graphical abstract




El texto completo de este artículo está disponible en PDF.

Key words : Phosphoinositide 3-kinase, PIK3CD, activated PI3Kδ syndrome, CD4+ T-cell function, follicular helper T cells, humoral immunity, immune class regulation, humans, mouse models

Abbreviations used : APC, APDS, BM, CFSE, cTFH, FITC, FoxP3, GC, GOF, HEL, ICOS, KO, OVA, PC, PD-1, PE, PerCP, PI3K, PMA, TCR, TFH, Treg, WT


Esquema


 Supported by project grants 1088215 (to E.K.D. and C.S.M.) and 1127157 (to S.G.T., E.K.D., and C.S.M.), program grants (1016953 and 1113904 to S.G.T. and R.B.), and Principal Research Fellowships (1042925 to S.G.T. and 1105877 to R.B.) from the National Health and Medical Research Council of Australia, the Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia to S.G.T.), the Office of Health and Medical Research of the NSW Government, the Jeffrey Modell Foundation, the John Cook Brown Foundation, and a Bench to Bedside grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH; to S.G.T., G.U., and L.D.N.). C.S.M. is supported by an Early-Mid Career Research Fellowship from the New South Wales State Government. J.B. is supported by the Postgraduate Research Scholarship awarded by Fundação Estudar (Brazil). A.L. is supported by a Tuition Fee Scholarship from UNSW Sydney. S.M.H., L.D.N., and G.U. are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
 Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.


© 2019  American Academy of Allergy, Asthma & Immunology. Reservados todos los derechos.
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