Immunoglobulin G Enhances Generation of Inducible T Regulatory Cells and Increases Their Regulatory Function

Intravenous immunoglobulin (IVIg) has been shown to be effective in the treatment of a variety of autoimmune diseases. To clarify the role of T regulatory cells (Tregs) in the immunoregulatory effect of IVIg, we focused on human inducible T regulatory cells (iTregs) and investigated the mechanism of action of IVIg. When immunoglobulin G (IgG) was added to a culture system that differentiates iTregs from anti-CD3 antibody activated CD4+CD25- T cells in the presence of syngeneic immature dendritic cells, interleukin (IL)-2 and transforming growth factor-β (TGF-β), the expression of forkhead box P3 (FoxP3), which is the master transcription factor for Tregs in CD4+CD25+ T cells, increased in an IgG concentration-dependent manner. The expression of FoxP3 in iTregs in the 20 mg/mL IgG group was twice as high as that in the saline group. iTregs that highly expressed FoxP3 not only partially suppressed the polyclonal proliferative response of T cells derived from the same individual but also produced significantly more inhibitory cytokines IL-10 and TGF-β. The ability of IgG to enhance iTregs differentiation was also observed in the Fc fragment, but not in the F(ab')2 fragment. These results suggest the clinical regulation of immune responses by IVIg administration may contribute at least to enhancing the differentiation of iTregs and partial immunosuppressive functions.