Tregitope mechanism of action and applications for tolerance induction.

Tregitopes are T cell epitopes naturally located in immunoglobulins that bind to multiple MHC Class II alleles and induce regulatory T cell (Treg) responses. Harnessing tolerogenic effects of Tregitopes provides a novel tool to suppress unwanted immune responses and maintain antigen-specific tolerance, thus changing treatment paradigms in autoimmunity. We have now demonstrated that APCs present Tregitopes to natural (n) Treg, engage feedback mechanisms promoting a tolerogenic APC phenotype, induce Treg expansion, and modulate antigen-specific effector T cell responses. Proportions of APC expressing MHC II, CD80, and CD86 are suppressed, consistent with reported effects of IVIG (Bayry et al. Blood, 2003, 101:758) and of the IgG-derived peptide hCDR1 (Sela et al. Immunology, 2009, 128:395). Moreover, we observed significant increases in proportions of IL-10-producing CD4+CD25+ FoxP3-expressing nTreg in the presence of Tregitopes. These studies are an exciting first step towards understanding the basic mechanism of Tregitope tolerance induction that we propose to be as follows: 1) APC present Tregitopes to nTreg, 2) nTreg are activated to proliferate and produce IL-10, 3) nTreg provide tolerogenic feedback signals to APC, modulating the APC phenotype, and 4) nTreg and tolerogenic APC together suppress antigen-specific T cell responses. These data suggest a role for Tregitopes in the mechanism of action for IVIG, and provide insight critical for future therapeutic applications.