Lactoferrin-derived Chimeric Peptide (LFch) boosts TGFβ1-induced Treg Differentiation by diminishing of TCR Signal intensity via TβRIII

Abstract Regulatory T cells (Tregs) are a special subset of T cells to suppress excessive immune response and maintain immunologic tolerance. It is known that lesser TCR signal strength is favorable for Foxp3+ Treg differentiation. We recently reported that LF substantially promoted Foxp3 expression by activated CD4+ T cells and this activity was further enhanced by TGF-β1. In the present study, we explored the effect of lactoferrin chimera (LFch, synthetic LF-derived chimeric peptides) along with TGFβ1 on Foxp3+ Treg differentiation. LFch itself did not induce Foxp3 expression. However, LFch dramatically enhanced TGFβ1-induced Foxp3 expression. LFch little affected the phosphorylation of Smad3, which is a canonical TGF-β1 mediator. Instead, LFch decreased the phosphorylation of S6, IkB, and PI3 kinase (an activation hallmark of TCR signaling). These effects of LFch were completely abolished by pretreatment of LFch with soluble TβRIII. Consistently, the enhancement of TGFβ1-induced Foxp3 by LFch was also abrogated by treatment of soluble TβRIII. Finally, TGFβ1/LFch-induced T cell population substantially suppressed the proliferation of responder CD4+ T cells. These results indicate that LFch potently enhances TGFβ1-induced Foxp3+ Treg differentiation by diminishing TCR signal intensity through TβRIII.