Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se

Tregitopes are a set of epitopes, derived from IgG, that bind to MHCII, activate nTregs, and promote tolerance. We have now confirmed that coadministration of Tregitopes with a range of proteins (autoantigens and nominal antigens, such as OVA) in vitro and in vivo leads to suppression of T cell and antibody responses to the test antigens. In this study, we demonstrate that Tregitopes are not immunogenic in vivo even when emulsified with strong adjuvants, such as IFA or CFA. Moreover, in vivo administration of Tregitopes with IFA or CFA does not induce Th1 or Th2 cytokine expression under restimulation conditions in vitro. We investigated tolerance induction by codelivering Tregitopes with OVA using B cells. When B cells were pulsed with OVA plus Tregitopes and transferred into naïve mice, we found that cellular and humoral immune responses to the OVA were suppressed. As a result of their ability to induce Tregs and the absence of immunogenicity in the context of strong adjuvants, Tregitopes might be considered a novel immunomodulatory approach for the suppression of immune responses to protein therapeutics (such as FVIII and mAb), as well as for treatment of autoimmune diseases

Activation of natural regulatory T cells by IgG Fc-derived peptide Tregitopes

We have identified at least 2 highly promiscuous major histocompatibility complex class II T-cell epitopes in the Fc fragment of IgG that are capable of specifically activating CD4+CD25HiFoxP3+ natural regulatory T cells (nTRegs). Coincubation of these regulatory T-cell epitopes or “Tregitopes” and antigens with peripheral blood mononuclear cells led to a suppression of effector cytokine secretion, reduced proliferation of effector T cells, and caused an increase in cell surface markers associated with TRegs such as FoxP3. In vivo administration of the murine homologue of the Fc region Tregitope resulted in suppression of immune response to a known immunogen. These data suggest that one mechanism for the immunosuppressive activity of IgG, such as with IVIG, may be related to the activity of regulatory T cells. In this model, regulatory T-cell epitopes in IgG activate a subset of nTRegs that tips the resulting immune response toward tolerance rather than immunogenicity

CD8+ regulatory T cells are responsible for GAD-IgG gene-transferred tolerance induction in NOD mice

Our previous studies demonstrated that lipopolysaccharide (LPS)-stimulated splenocytes, retrovirally transduced with a glutamate decarboxylate 65 (GAD) and immunoglobulin G (IgG) fusion construct, can protect non-obese diabetic (NOD) mice from diabetes by inducing GAD-specific tolerance, and also that there are increased numbers of CD4+ regulatory T cells (Tregs) in GAD-IgG-treated NOD mice. However, little is known about the role of CD8+ Tregs in GAD-IgG gene-transferred tolerance induction in NOD mice. Here, we found that GAD-IgG-transduced splenocytes induced an increase in the number of CD8+ Foxp3+ Tregs in vitro. Using a T-cell depletion assay, we found that, compared with undepleted groups, NOD recipients transfused with CD8− or CD8− CD25− GAD-IgG-transduced splenocytes showed a decrease in the percentage of CD8+ Foxp3+ T cells, a high incidence of diabetes, serious insulitis, GAD-specific hyperresponsiveness at both the cellular and humoral levels, and changes in cytokine expression. These results indicate that CD8+ Tregs, which were induced in vitro by GAD-IgG-transduced splenocytes, were also responsible for GAD-IgG gene-transferred tolerance induction in NOD mice