Tregitopes: The active ingredient in IVIG-mediated tolerance induction? (P5224)

Abstract

Abstract In the course of screening IgG sequences for T cell epitopes, we identified Treg epitope peptides, now called Tregitopes, contained in conserved framework regions of Fab and Fc. Tregitopes may provide one explanation for the expansion and stimulation of Treg following intravenous immunoglobulin (IVIg) therapy. Their distinguishing characteristics include in silico signatures of high-affinity binding to multiple human HLA class II DR, and conservation across IgG isotypes as well as mammalian species. Tregitopes induce expansion of CD4+/CD25hi/FoxP3+ T cells and suppress immune responses to co-incubated antigens in vitro. Comparing human Tregitopes (hTregitopes) to murine sequences, we identified class II-restricted murine Tregitope homologs (mTregitopes). We provide evidence that when APCs present Tregitopes to natural (n) Treg, APC expression of MHC II, CD80, and CD86 are decreased. Moreover, Tregitopes increase proportions of IL-10-producing nTreg. We propose the mechanism of Tregitope-mediated tolerance induction to be as follows: 1) APC present Tregitopes to nTreg, 2) nTreg are activated, 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. The discovery of Tregitopes in IgG and other autologous proteins may lead to the development of new insights as to the role of Tregs in autoimmune diseases.