title: IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts.
abstract: B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common γ chain (γc)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Rα) in normal, but not STAT3-deficient, CD40L-stimulated naïve B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naïve B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;
authors.forename: Lucinda J
authors.initials: LJ
authors.lastname: Berglund
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Leen
authors.initials: L
authors.lastname: Moens
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Stephen
authors.initials: S
authors.lastname: Adelstein
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Liliana
authors.initials: L
authors.lastname: Bezrodnik
authors.forename: Harjit
authors.initials: H
authors.lastname: Dadi
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: John B
authors.initials: JB
authors.lastname: Ziegler
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smart
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects; D000098546:Interleukin-21
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D023201:CD40 Ligand; D000098546:Interleukin-21