title: B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans.
abstract: Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
authors.affiliation: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Santi
authors.initials: S
authors.lastname: Suryani
authors.forename: Nicholas
authors.initials: N
authors.lastname: Simpson
authors.forename: Gary Y
authors.initials: GY
authors.lastname: Chew
authors.forename: Tyani D
authors.initials: TD
authors.lastname: Chan
authors.forename: Umamainthan
authors.initials: U
authors.lastname: Palendira
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.forename: Karl E
authors.initials: KE
authors.lastname: Bleasel
authors.forename: Jane
authors.initials: J
authors.lastname: Peake
authors.forename: Cecile
authors.initials: C
authors.lastname: King
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.forename: Dan
authors.initials: D
authors.lastname: Engelhard
authors.forename: Sami
authors.initials: S
authors.lastname: Al-Hajjar
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Klaus
authors.initials: K
authors.lastname: Magdorf
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Pravin
authors.initials: P
authors.lastname: Hissaria
authors.forename: D Sean
authors.initials: DS
authors.lastname: Riminton
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D000917:Antibody Formation / Q000502:physiology; D000941:Antigens / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000502:physiology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D000098546:Interleukin-21
chemical_list: D000941:Antigens; D007136:Immunoglobulins; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21