A Novel Model of IVIG Immunosuppression: Activation of Natural Regulatory T cells by IgG‐Derived Peptides

Abstract

Background. Intravenous IgG (IVIG) is widely used to suppress immune responses in autoimmune diseases, allergy and transplantation. However, the exact mechanism responsible for its immunosuppressive/tolerogenic activity remains unknown. We hypothesized that the immunosuppressive effect of IVIG may be due to the presence of T cell epitopes in IgG that are capable of activating natural regulatory T cells (Tregs), leading to the suppression of T effector immune responses.Methods and Results. Using the EpiMatrix algorithm, we identified three highly promiscuous MHC Class II T‐cell epitopes in both the heavy and light chain constant domains of IgG. These epitopes were shown to bind multiple HLA Class II molecules with high affinity and specifically upregulated FoxP3 expression in CD4+CD25high T cells. Co‐administration with various antigens led to suppression of effector T cell responses an increase in IL‐10 and CTLA‐4 expression.Discussion. We believe that these data point to a previously undescribed mechanism for the immunosuppressive activity of IVIG. In this model, regulatory T‐cell epitopes (Tregitopes) in IgG are co‐processed and co‐presented with immunogenic epitopes derived from an antigen. The IgG Tregitopes activate a subset of natural regulatory T cells that can, at low dose of antigen, tip the resulting immune response towards tolerance rather than immunogenicity.All work was funded by EpiVax Inc.