Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function

M.L. Ives, C.S. Ma, U. Palendira, A. Chan, J.C. Bustamante, S. Boisson-Dupuis, P.D. Arkwright, D. Engelhard, D. Averbuch, K. Magdorf, J.R. Roesler, J.E. Peake, M. Wong, S. Adelstein, S. Choo, J.M. Smart, Martyn French, D.A. Fulcher, M. Cook, C. PïcardA.H. Durandy, M. Tsumura, M. Kobayashi, G. Uzel, J.L. Casanova., S.G. Tangye, E.K.K. Deenick

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    39 Citations (Scopus)

    Abstract

    Background
    The capacity of CD8+T cells to control infections and mediate anti-tumor immunity requires
    the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8+ T cell effector function
    and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T cell immunity in humans is unknown.ObjectiveTo determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease
    pathogenesis in primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade.

    Methods
    Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules
    in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in STAT1, STAT3 or IL21R were used to assess the respective roles of these genes in human CD8+ T cell differentiation in vivo and in vitro.

    Results
    Mutations in STAT3 and IL21R, but not STAT1, lead to a decrease in multiple memory CD8+ T cell subsets in vivo, indicating that STAT3 signaling – possibly downstream of IL-21R - regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naïve CD8+ T cells. However, this defect was overcome by TCR engagement.

    Conclusion
    The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3 and IL-21R-deficient individuals.
    Original languageEnglish
    Pages (from-to)400-411
    JournalJournal of Allergy and Clinical Immunology
    Volume132
    Issue number2
    Early online date4 Jul 2013
    DOIs
    Publication statusPublished - Aug 2013

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  • Cite this

    Ives, M. L., Ma, C. S., Palendira, U., Chan, A., Bustamante, J. C., Boisson-Dupuis, S., Arkwright, P. D., Engelhard, D., Averbuch, D., Magdorf, K., Roesler, J. R., Peake, J. E., Wong, M., Adelstein, S., Choo, S., Smart, J. M., French, M., Fulcher, D. A., Cook, M., ... Deenick, E. K. K. (2013). Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function. Journal of Allergy and Clinical Immunology, 132(2), 400-411. https://doi.org/10.1016/j.jaci.2013.05.029