IL-21 is a broad negative regulator of IgE class switch recombination in mouse and human B cells

• Published in: The Journal of experimental medicine Vol. 217; no. 5
• Main Authors: Yang, Zhiyong, Wu, Chung-An M., Targ, Sasha, Allen, Christopher D.C.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.05.2020
• Subjects: Animals; Apoptosis; B-Lymphocytes - immunology; CD40 Antigens - metabolism; Cell Count; Germinal Center - cytology; Humans; Immunity; Immunodeficiency; Immunoglobulin Class Switching - genetics; Immunoglobulin E - genetics; Immunoglobulin G - metabolism; Interferon-gamma - metabolism; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Interleukins - metabolism; Lymph Nodes - cytology; Mice; Models, Biological; Plasma Cells - metabolism; Receptors, Interleukin-21 - metabolism; Signal Transduction; STAT3 Transcription Factor - metabolism; T Follicular Helper Cells - metabolism
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20190472

IgE antibodies may elicit potent allergic reactions, and their production is tightly controlled. The tendency to generate IgE has been thought to reflect the balance between type 1 and type 2 cytokines, with the latter promoting IgE. Here, we reevaluated this paradigm by a direct cellular analysis, demonstrating that IgE production was not limited to type 2 immune responses yet was generally constrained in vivo. IL-21 was a critical negative regulator of IgE responses, whereas IFN-γ, IL-6, and IL-10 were dispensable. Follicular helper T cells were the primary source of IL-21 that inhibited IgE responses by directly engaging the IL-21 receptor on B cells and triggering STAT3-dependent signaling. We reconciled previous discordant results between mouse and human B cells and revealed that the inhibition of IgE class switch recombination by IL-21 was attenuated by CD40 signaling, whereas IgG1 class switch recombination was potentiated by IL-21 in the context of limited IL-4. These findings establish key features of the extrinsic regulation of IgE production by cytokines.