Type I IFN facilitates the expansion of CD4+CD25+Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells (143.13)

Abstract

Abstract Interferon-beta (IFN-β) is a disease-modifying agent used in the treatment for multiple sclerosis (MS). Its mechanisms are complex and still not fully understood. It was observed clinically that the number of CD4+CD25+FOXP3+ regulatory T cells increase in patients treated with IFN-β for over 6 months. Here we demonstrate that IFN-β-induced up-regulation of glucocorticoid-induced TNF receptor ligand (GITRL) on dendritic cells (DC) promotes the proliferation of anergic Treg cells in mice. In vitro treatment of DC with IFN-β increases the expression of GITRL at both mRNA (by ~5 folds in PCR) and protein level (by ~25% in flow cytometry). Purified Treg cells, when stimulated with anti-CD3 and anti-CD28 Abs, remarkably proliferate in the presence of IFN-β pretreated DC. Blockade of GITRL with antibody diminishes the ability of DC to stimulate Treg cell proliferation. IFN-β shows no effect on the TGF-β induced conversion of CD4+CD25- T cells to Foxp3+ Treg cells in mice. DCs of IFNAR-/- mice are less potent in facilitating the proliferation of Treg cells. Treatment of EAE mice with mIFN-β for 2 months results in the upregulation of peripheral Foxp3+ Treg cells. However, in mice depleted with DC by liposomal clodronate treatment, IFN-β failed to induce the increase of Treg cells in vivo. Our findings are not only essential for the understanding of the effect of IFN-β in the treatment for MS but also provide insight into how Treg cells accordingly respond to inflammation.