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• W2082174358 endingPage "411.e9" @default.
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• W2082174358 abstract "BackgroundThe capacity of CD8+ 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+ 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 human subjects is unknown.ObjectiveWe sought to 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 patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade.MethodsHuman 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+ T-cell differentiation in vivo and in vitro.ResultsMutations in STAT3 and IL21R, but not STAT1, led 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 naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement.ConclusionThe 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 subjects. The capacity of CD8+ 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+ 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 human subjects is unknown. We sought to 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 patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. 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+ T-cell differentiation in vivo and in vitro. Mutations in STAT3 and IL21R, but not STAT1, led 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 naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement. 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 subjects." @default.
• W2082174358 created "2016-06-24" @default.
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• W2082174358 date "2013-08-01" @default.
• W2082174358 modified "2023-10-18" @default.
• W2082174358 title "Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function" @default.
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