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Functional STAT3 deficiency compromises the generation of human T follicular helper cells

Ma, Cindy; Avery, Danielle T; Chan, Anna; Batten, Marcel L; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Arkwright, Peter D; Kreins, Alexandra Y; Averbuch, Diana; Engelhard, Dan; Cook, Matthew; Deenick, Elissa; Tangye, Stuart

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T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4 + T cells to the Tfh lineage, because IL-12 induces naive human CD4 + T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have...[Show more]

dc.contributor.authorMa, Cindy
dc.contributor.authorAvery, Danielle T
dc.contributor.authorChan, Anna
dc.contributor.authorBatten, Marcel L
dc.contributor.authorBustamante, Jacinta
dc.contributor.authorBoisson-Dupuis, Stephanie
dc.contributor.authorArkwright, Peter D
dc.contributor.authorKreins, Alexandra Y
dc.contributor.authorAverbuch, Diana
dc.contributor.authorEngelhard, Dan
dc.contributor.authorCook, Matthew
dc.contributor.authorDeenick, Elissa
dc.contributor.authorTangye, Stuart
dc.date.accessioned2015-12-10T23:02:11Z
dc.identifier.issn0006-4971
dc.identifier.urihttp://hdl.handle.net/1885/61901
dc.description.abstractT follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4 + T cells to the Tfh lineage, because IL-12 induces naive human CD4 + T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4 + T cells from patients deficient in IL-12Rp1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4 + T cells. Defective expression of IL-21 by STAT3-deficient CD4 + T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4 +CXCR5 + T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
dc.publisherAmerican Society of Hematology
dc.sourceBlood
dc.subjectKeywords: chemokine receptor CXCR5; interleukin 12; interleukin 12 receptor beta1; interleukin 21; protein bcl 6; protein kinase TYK2; STAT1 protein; STAT3 protein; adolescent; adult; article; B lymphocyte; CD4+ T lymphocyte; cell line; cell lineage; cell maturatio
dc.titleFunctional STAT3 deficiency compromises the generation of human T follicular helper cells
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume119
dc.date.issued2012
local.identifier.absfor110200 - CARDIOVASCULAR MEDICINE AND HAEMATOLOGY
local.identifier.ariespublicationf5625xPUB649
local.type.statusPublished Version
local.contributor.affiliationMa, Cindy, Garvan Institute of Medical Research
local.contributor.affiliationAvery, Danielle T, Garvan Institute of Medical Research
local.contributor.affiliationChan, Anna , Garvan Institute of Medical Research
local.contributor.affiliationBatten, Marcel L, Garvan Institute of Medical Research
local.contributor.affiliationBustamante, Jacinta, Necker Medical School, University of Paris Descartes
local.contributor.affiliationBoisson-Dupuis, Stephanie, Necker Medical School, University of Paris Descartes
local.contributor.affiliationArkwright, Peter D, University of Manchester
local.contributor.affiliationKreins, Alexandra Y, The Rockefeller University
local.contributor.affiliationAverbuch, Diana, Hadassah-Hebrew University Medical Centre
local.contributor.affiliationEngelhard, Dan, Hadassah-Hebrew University Medical Centre
local.contributor.affiliationCook, Matthew, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationMa, Cindy , Garvan Institute of Medical Research
local.contributor.affiliationDeenick, Elissa, Garvan Institute of Medical Research
local.contributor.affiliationTangye, Stuart, Garvan Institute of Medical Research
local.description.embargo2037-12-31
local.bibliographicCitation.issue17
local.bibliographicCitation.startpage3997
local.bibliographicCitation.lastpage4008
local.identifier.doi10.1182/blood-2011-11-392985
dc.date.updated2016-06-14T08:36:38Z
local.identifier.scopusID2-s2.0-84859711557
local.identifier.thomsonID000305282900021
CollectionsANU Research Publications

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