title: STAT3 is required for IL-21-induced secretion of IgE from human naive B cells.
abstract: The production of immunoglobulin E (IgE) is tightly regulated. This is evidenced by the fact that it comprises less than 0.0001% of serum Ig, and aberrant production causes atopic conditions, including allergy, rhinitis, and anaphylaxis. Interleukin-4 (IL-4) is a well-characterized inducer of IgE by human and murine B cells, whereas interferon-gamma can antagonize this effect. IL-21 has also been recognized for its ability to suppress IL-4-induced IgE production by murine B cells. Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells. Furthermore, there was a striking synergy between IL-4 and IL-21 on inducing IgE secretion by CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by more than 10-fold. IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent. These findings highlight a fundamental difference between the regulation of IgE production by human and murine B cells and have implications for the dysregulated production of IgE in conditions characterized by extremely high levels of serum IgE.
authors.affiliation: Immunology and Inflammation Group, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Bryant
authors.forename: Brigitte
authors.initials: B
authors.lastname: Santner-Nanan
authors.forename: Ralph
authors.initials: R
authors.lastname: Nanan
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D007378:Interleukins / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017455:Receptors, IgE / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D000098546:Interleukin-21
chemical_list: C508609:IL10 protein, human; C508598:IL4 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D007378:Interleukins; D017455:Receptors, IgE; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D023201:CD40 Ligand; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D000098546:Interleukin-21