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

Background: The capacity of CD8 super(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8 super(+) T-cell effector function and memory development in mouse models of infectiou...

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Published in:Journal of allergy and clinical immunology 2013-08, Vol.132 (2), p.400-411.e9
Main Authors: Ives, Megan L, Ma, Cindy S, Palendira, Umaimainthan, Chan, Anna, Bustamante, Jacinta, Boisson-Dupuis, Stephanie, Arkwright, Peter D, Engelhard, Dan, Averbuch, Diana, Magdorf, Klaus, Roesler, Joachim, Peake, Jane, Wong, Melanie, Adelstein, Stephen, Choo, Sharon, Smart, Joanne M, French, Martyn A, Fulcher, David A, Cook, Matthew C, Picard, Capucine, Durandy, Anne, Tsumura, Miyuki, Kobayashi, Masao, Uzel, Gulbu, Casanova, Jean-Laurent, Tangye, Stuart G, Deenick, Elissa K
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Language:English
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Summary:Background: The capacity of CD8 super(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8 super(+) 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 super(+) T-cell immunity in human subjects is unknown. Objective: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8 super(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with 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 signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8 super(+) T-cell differentiation in vivo and in vitro. Results: Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8 super(+) 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 naive CD8 super(+) T cells. However, this defect was overcome by T-cell receptor engagement. Conclusion: The IL-21R/STAT3 pathway is required for many aspects of human CD8 super(+) 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 subjects.
ISSN:0091-6749
DOI:10.1016/j.jaci.2013.05.029