Tregitopes and impaired antigen presentation: Drivers of the immunomodulatory effects of IVIg?

Introduction Although intravenous immunoglobulin (IVIg) is commonly used in the clinic to treat various autoimmune and severe inflammatory diseases, the mode of action is not fully elucidated. This work investigates two proposed mechanisms: (1) the potential role of regulatory T‐cell epitopes (Tregitopes) from the constant domain of IgG in the immunosuppressive function of IVIg; and (2) a potential impact of IVIg on the ability of antigen presenting cells (APCs) to present peptides. Methods and Results Investigation of the HLA class II peptide repertoire from IVIg‐loaded dendritic cells (DCs) via MHC‐associated peptide proteomics (MAPPs) revealed that numerous IgG‐derived peptides were strongly presented along the antibody sequence. Surprisingly, Tregitopes 167 and 289 did not show efficient natural presentation although they both bound to HLA class II when directly loaded as “naked” peptides on human DCs. In addition, both Tregitopes could not reproduce the inhibitory effect of IVIg in a human in vitro T‐cell proliferation assay as well as in vivo in mice. MAPPs data demonstrate that presentation of peptides from several antigens remained unchanged even when competed with high doses of IVIg, in both human and mouse. Conclusion These data suggest that the effects mediated by IVIg are not caused by Tregitopes nor by impaired antigen presentation. This manuscript investigates two published mechanisms, by which IVIg may exert its immunosuppressive function (1) via regulatory T‐cell epitopes (Tregitopes) or via competition of IVIg with antigens for antigen presentation. We found that Tregitopes are not well presented in vitro and in vivo when enzymatic antigen processing is required. In our hands, Tregitopes did not suppress antigen‐specific T‐cell proliferation in vitro in human PBMCs or antigen‐specific antibody formation in vivo in mice. We show that even high doses of IVIg did not alter peptide presentation of other proteins in vitro and in vivo, which speaks against a competition of IVIg on the antigen presentation level.