Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-β signaling

Mucosal Immunol. 2015 Jul;8(4):906-17. doi: 10.1038/mi.2014.121. Epub 2014 Dec 10.


Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-β1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-β receptor III, TβRIII) and in turn induced phosphorylation of TβRI and Smad3 through formation of the TβRIII/TβRII/TβRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • Antibody Formation / drug effects
  • Antibody Formation / immunology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Immunity, Mucosal
  • Immunoglobulin A / biosynthesis
  • Immunoglobulin A / immunology*
  • Immunoglobulin Class Switching* / drug effects
  • Immunoglobulin Class Switching* / immunology
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / immunology*
  • Lactoferrin / metabolism*
  • Lactoferrin / pharmacology
  • Mice
  • Protein Binding
  • Proteoglycans / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction* / drug effects
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology


  • Adjuvants, Immunologic
  • Immunoglobulin A
  • Immunoglobulin G
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Smad3 Protein
  • Transforming Growth Factor beta
  • betaglycan
  • Lactoferrin