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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.

Journal of allergy and clinical immunology, 2019-07, Vol.144 (1), p.236-253 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4+ T cells
Autor: 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.
Assuntos: 1-Phosphatidylinositol 3-kinase ; activated PI3Kδ syndrome ; Animals ; Antigens ; Apoptosis ; CD4 antigen ; CD4+ T-cell function ; CD4-Positive T-Lymphocytes - metabolism ; CD8 antigen ; Cell activation ; Cell death ; Cell Differentiation ; CXCR3 protein ; Cytokines ; Cytokines - metabolism ; Defects ; Differentiation ; follicular helper T cells ; Gain of Function Mutation ; Genotype & phenotype ; Humans ; humoral immunity ; immune class regulation ; Immune response (humoral) ; Immunodeficiency ; Immunological memory ; Infections ; Kinases ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Memory cells ; Mice ; mouse models ; Mutation ; Pathogenesis ; Phenotype ; Phenotypes ; Phosphatidylinositol 3-Kinases - genetics ; Phosphoinositide 3-kinase ; PIK3CD ; Primary immunodeficiencies ; Proteins ; Respiratory tract ; Respiratory tract diseases ; Viral infections ; γ-Interferon
É parte de: Journal of allergy and clinical immunology, 2019-07, Vol.144 (1), p.236-253
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SourceType-Scholarly Journals-1
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Descrição: 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. We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. 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. 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. 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. [Display omitted]
Editor: United States: Elsevier Inc
Idioma: Inglês

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

United States: Elsevier Inc

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