title: Functional STAT3 deficiency compromises the generation of human T follicular helper cells.
abstract: 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 now examined CD4(+) T cells from patients deficient in IL-12Rβ1, 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.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, 2010 NSW, Australia. c.ma@garvan.org.au
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Anna
authors.initials: A
authors.lastname: Chan
authors.forename: Marcel
authors.initials: M
authors.lastname: Batten
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Alexandra Y
authors.initials: AY
authors.lastname: Kreins
authors.forename: Diana
authors.initials: D
authors.lastname: Averbuch
authors.forename: Dan
authors.initials: D
authors.lastname: Engelhard
authors.forename: Klaus
authors.initials: K
authors.lastname: Magdorf
authors.forename: Sara S
authors.initials: SS
authors.lastname: Kilic
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smart
authors.forename: Jane
authors.initials: J
authors.lastname: Peake
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Paul
authors.initials: P
authors.lastname: Gray
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D016867:Immunocompromised Host; D018664:Interleukin-12 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D009154:Mutation / Q000235:genetics*; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D053634:TYK2 Kinase / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D018664:Interleukin-12; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse