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Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD81 T-cell memory formation and function

Ives, Megan L; Ma, Cindy; 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; Cook, Matthew C; Picard, Capucine; Durandy, Anne; Tsumura, Miyuki; Kobayashi, Masao; Uzel, Gulbu; Casanova, Jean-Laurent; Tangye, Stuart G; Deenick, Elissa K

Description

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...[Show more]

dc.contributor.authorIves, Megan L
dc.contributor.authorMa, Cindy
dc.contributor.authorPalendira, Umaimainthan
dc.contributor.authorChan, Anna
dc.contributor.authorBustamante, Jacinta
dc.contributor.authorBoisson-Dupuis, Stephanie
dc.contributor.authorArkwright, Peter D
dc.contributor.authorEngelhard, Dan
dc.contributor.authorAverbuch, Diana
dc.contributor.authorMagdorf, Klaus
dc.contributor.authorRoesler, Joachim
dc.contributor.authorPeake, Jane
dc.contributor.authorWong, Melanie
dc.contributor.authorAdelstein, Stephen
dc.contributor.authorChoo, Sharon
dc.contributor.authorSmart, Joanne M.
dc.contributor.authorFrench, Martyn A
dc.contributor.authorFulcher, David
dc.contributor.authorCook, Matthew C
dc.contributor.authorPicard, Capucine
dc.contributor.authorDurandy, Anne
dc.contributor.authorTsumura, Miyuki
dc.contributor.authorKobayashi, Masao
dc.contributor.authorUzel, Gulbu
dc.contributor.authorCasanova, Jean-Laurent
dc.contributor.authorTangye, Stuart G
dc.contributor.authorDeenick, Elissa K
dc.date.accessioned2014-02-23T23:19:03Z
dc.date.available2014-02-23T23:19:03Z
dc.identifier.issn0091-6749
dc.identifier.urihttp://hdl.handle.net/1885/11409
dc.description.abstractBackground 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.
dc.description.sponsorshipSupported by project and program grants from the National Health and Medical Research Council (NHMRC) of Australia (to E.K.D., S.G.T., C.S.M., D.A.F., and M.C.C.), Cancer Council NSW (to S.G.T. and U.P.), and Rockefeller University Center for 541 Clinical and Translational science (5UL1RR024143, to J.-L.C.). C.S.M. is a recipient of a Career Development Fellowship and S.G.T. is a recipient of a Principal Research Fellowship from the NHMRC of Australia. Disclosure of potential conflict of interest: C. S. Ma has been supported by one or more grants from the National Health and Medical Research Council of Australia (NHMRC). J. Peake has received one or more payments for lecturing on allergy topics and has been reimbursed for travel/accommodations/meeting expenses. M. A. French has received one or more payments for lecturing from or is on the speakers’ bureau for ViiV Australia, MSD Australia, and Janssen Australia and has received one or more payments for travel/accommodations/meeting expenses from MSD Australia and ViiVAustralia. J.-L. Casanova has been supported by one or more grants from the National Institutes of Health (grant no. 8UL1TR000043); has consultancy arrangements with Regeneron, GlaxoSmithKline, NovImmune, BiogenIdec, Merck, and Sanofi- Aventis; and has received one or more grants from or has one or more grants pending with Merck. S. G. Tangye has been supported by one or more grants from the NHMRC of Australia; has received support for travel from ESID, Keystone Symposia, and the Jeffrey Modell Foundation; and has received one or more fees for serving as an expert witness in a patent dispute. E. K. Deenick has been supported by one or more grants from NHMRC, has received one or more payments for travel/accommodations/meeting expenses from the Japanese Society for Immunology, and has received one or more paid honoraria as an Editor for Immunology and Cell Biology. The rest of the authors declare that they have no relevant conflicts of interest.
dc.format21 pages
dc.publisherElsevier
dc.rightshttp://www.sherpa.ac.uk/romeo/issn/0091-6749/author can archive pre-print (ie pre-refereeing);author cannot archive publisher's version/PDF
dc.sourceJournal of Allergy and Clinical Immunology 132.2 (2013): 400–411.e9
dc.subjectAutosomal dominant hyper-IgE syndrome
dc.subjectSTAT3
dc.subjectSTAT1
dc.subjectIL-21; human CD8+ T cells
dc.subjectmemory
dc.subjectdifferentiation
dc.titleSignal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD81 T-cell memory formation and function
dc.typeJournal article
local.identifier.citationvolume132
dcterms.dateAccepted2013-05-16
dc.date.issued2013-08
local.identifier.absfor110700 - IMMUNOLOGY
local.identifier.ariespublicationf5625xPUB4237
local.publisher.urlhttp://www.elsevier.com/
local.type.statusPublished Version
local.contributor.affiliationCook, Matthew C, Australian National University Medical School and the John Curtin School of Medical Research, Australian National University
local.bibliographicCitation.issue2
local.bibliographicCitation.startpage400
local.bibliographicCitation.lastpage411
local.identifier.doi10.1016/j.jaci.2013.05.029
dc.date.updated2015-12-11T08:48:26Z
local.identifier.scopusID2-s2.0-84881121485
local.identifier.thomsonID000322631700018
CollectionsANU Research Publications

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