STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

• Published in: Blood 2008-09, Vol.112 (5), p.1784-1793
• Main Authors: Avery, Danielle T., Ma, Cindy S., Bryant, Vanessa L., Santner-Nanan, Brigitte, Nanan, Ralph, Wong, Melanie, Fulcher, David A., Cook, Matthew C., Tangye, Stuart G.
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Antibody production; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - physiology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD40 Ligand - pharmacology; Cell Differentiation; Cell Division; Cells, Cultured; Fetal Blood - cytology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Immunoglobulin E - biosynthesis; In Vitro Techniques; Infant, Newborn; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-4 - physiology; Interleukin-6 - physiology; Interleukins - chemistry; Interleukins - pharmacology; Interleukins - physiology; Job Syndrome - genetics; Job Syndrome - immunology; Mice; Mutation; Phosphorylation; Receptors, IgE - metabolism; Species Specificity; STAT3 Transcription Factor - deficiency; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-02-142745

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-γ 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.