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


BACKGROUND: 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. OBJECTIVE: 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. 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(+) 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(+) 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. 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 subjects.

Type Journal
Authors Ives, M. L.; Ma, C. S.; Palendira, U.; Chan, A.; Bustamante, J.; Boisson-Dupuis, S.; Arkwright, P. D.; Engelhard, D.; Averbuch, D.; Magdorf, K.; Roesler, J.; Peake, J.; Wong, M.; Adelstein, S.; Choo, S.; Smart, J. M.; French, M. A.; Fulcher, D. A.; Cook, M. C.; Picard, C.; Durandy, A.; Tsumura, M.; Kobayashi, M.; Uzel, G.; Casanova, J. L.; Tangye, S. G.; Deenick, E. K.;
Responsible Garvan Author (missing name)
Published Date 2013-08-01
Published Volume 132
Published Issue 2
Published Pages 400-411 e9
Status Published in-print
DOI 10.1016/j.jaci.2013.05.029
URL link to publisher's version
OpenAccess link to author's accepted manuscript version