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Lactoferrin (LF) is known to possess anti-inflammatory activity, although its mechanisms of action are not well-understood. The present study asked whether LF affects the commitment of inducible regulatory T cells (Tregs). LF substantially promoted Foxp3 expression by mouse activated CD4 + T cells, and this activity was further enhanced by TGF-β1. Interestingly, blocking TGF-β with anti-TGF-β Ab completely abolished LF-induced Foxp3 expression. However, no significant amount of soluble TGF-β was released by LF-stimulated T cells, suggesting that membrane TGF-β (mTGF-β) is associated. Subsequently, it was found that LF binds to TGF-β receptor III, which induces reactive oxygen species production and diminishes the expression of mTGF-β-bound latency-associated peptide, leading to the activation of mTGF-β. It was followed by phosphorylation of Smad3 and enhanced Foxp3 expression. These results suggest that LF induces Foxp3 + Tregs through TGF-β receptor III/reactive oxygen species-mediated mTGF-β activation, triggering canonical Smad3-dependent signaling. Finally, we found that the suppressive activity of LF-induced Tregs is facilitated mainly by CD39/CD73-induced adenosine generation and that this suppressor activity alleviates inflammatory bowel disease., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Lactoferrin (LF) and retinoic acid (RA) are enriched in colostrum, milk, and mucosal tissues. We recently showed that LF-induced IgA class switching through binding to betaglycan (transforming growth factor-beta receptor III, TβRIII) and activation of canonical TGF-β signaling. We investigated the combined effect of LF and RA on the overall IgA response. An increase in IgA production by LF was further augmented by RA. This combination effect was also evident in Ig germ-line α (GLα) transcription and GLα promoter activity, indicating that LF in cooperation with RA increased IgA isotype switching. We subsequently found that RA enhanced TβRIII expression and that this increase contributed to LF-stimulated IgA production. In addition to the IgA response, LF and RA in combination also enhanced the expression of the gut-homing molecules C-C chemokine receptor 9 (CCR9) and α4β7 on B cells. Finally, peroral administration of LF and RA enhanced the frequency of CCR9 + IgA + plasma cells in the lamina propria. Taken together, these results suggest that LF in cooperation with RA can contribute to the establishment of gut IgA responses.

We recently reported that lactoferrin (LF) induces Foxp3+ Treg differentiation through binding to TGFβ receptor III (TβRIII), and this activity was further enhanced by TGFβ1. Generally, a low T‐cell receptor (TCR) signal strength is favourable for Foxp3+ Treg differentiation. In the present study, we explored the effect of lactoferrin chimera (LFch, containing lactoferricin [aa 17–30] and lactoferrampin [aa 265–284]), along with TGFβ1 on Foxp3+ Treg differentiation. LFch alone did not induce Foxp3 expression, yet LFch dramatically enhanced TGFβ1‐induced Foxp3 expression. LFch had little effect on the phosphorylation of Smad3, a canonical transcriptional factor of TGFβ1. Instead, LFch attenuated the phosphorylation of S6 (a target of mTOR), IκB and PI3K. These activities of LFch were completely abrogated by pretreatment of LFch with soluble TGFβ1 receptor III (sTβRIII). Consistent with this, the activity of LFch on TGFβ1‐induced Foxp3 expression was also abrogated by treatment with sTβRIII. Finally, the TGFβ1/LFch‐induced T cell population substantially suppressed the proliferation of responder CD4+ T cells. These results indicate that LFch robustly enhances TGFβ1‐induced Foxp3+ Treg differentiation by diminishing TCR/CD28 signal intensity. [ABSTRACT FROM AUTHOR]