Lactoferrin Potentiates Inducible Regulatory T Cell Differentiation through TGF-β Receptor III Binding and Activation of Membrane-Bound TGF-β

초록

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-beta 1. Interestingly, blocking TGF-beta with anti-TGF-beta Ab completely abolished LF-induced Foxp3 expression. However, no significant amount of soluble TGF-beta was released by LF-stimulated T cells, suggesting that membrane TGF-beta (mTGF-beta) is associated. Subsequently, it was found that LF binds to TGF-beta receptor III, which induces reactive oxygen species production and diminishes the expression of mTGF-beta-bound latency-associated peptide, leading to the activation of mTGF-beta. It was followed by phosphorylation of Smad3 and enhanced Foxp3 expression. These results suggest that LF induces Foxp3(+) Tregs through TGF-beta receptor III/reactive oxygen species-mediated mTGF-beta 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.

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