DCs are professional APCs for initiating both immune response and immune tolerance. Tolerogenic DCs are generally known as regulatory DCs that suppress immune responses through regulation of T cells such as induction of T cell anergy/apoptosis and Treg. Since we have demonstrated that lactoferrin (LF) induces functional Tregs and has a protective effect against IBD, we explored the tolerogenic effect of LF on mouse bone marrow-derived DC (BMDC) and its underlying mechanisms. LF enabled BMDCs to suppress the proliferation of allogenic CD4+ T cells, and elevated levels of Arg-1, IDO-1, and CD39/73 (known as key T cell suppressor molecules). Consistently, the suppressive activity of LF-treated DCs (LF-DCs) was disappeared by inhibitors of Arg-1 and CD39. Finally, LF-DCs enhanced TGFβ1-induced OVA-specific Foxp3+ T cell population.
Collectively, these results suggest that lactoferrin effectively causes DCs to be tolerogenic by both direct suppression of T cell proliferation and indirect enhancement of Treg differentiation.
We recently found that lactoferrin (LF), like TGF-β1, enhanced Ag non-specific Foxp3+ iTreg differentiation and the two molecules synergized to express Foxp3. In the present study, we investigated effect of LF and TGF-β1 on Ag-specific Foxp3+ iTreg differentiation. Naïve CD4+ T cells isolated from OT-II mice were co-cultured with OVA323–339-loaded T cell-depleted splenocytes as APCs. OVA-specific Foxp3+ Treg population was increased by LF and TGF-β1 alone, and synergistically increased by combination of the two molecules. However, these increases were diminished by additional CD28 stimulation using anti-CD28 Ab. In parallel, blockade of B7 molecules using CTLA4-Ig markedly increased the Foxp3 expression. These results imply that lactoferrin alone or particularly along with TGF-β1 can cause naïve T cells to differentiate into Foxp3+ Tregs, greater under weak co-stimulatory signals.
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