Antigens Bearing Synthetic Glycosylations Induce Lasting Antigen-Specific Tolerance and Prevent Autoimmunity

Homeostatic antigen presentation by hepatic antigen presenting cells (HAPCs) results in tolerogenic, and not effector, T cell education. For this reason, strategies that target antigens to HAPCs have the potential to induce antigen-specific immunological tolerance. Here, we show that antigens modified with synthetic polymeric glycosylations composed of either NAc-galactosamine or NAc-glucosamine target HAPCs, and thus induce antigen-specific tolerance as indicated by CD4⁺ and CD8⁺ T cell deletion and senescence and the induction of CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs). Glycopolymer-modified antigens expanded Tregs, which were necessary for long-term suppression of antigen-specific immune responses. Using an adoptive transfer model of type 1 diabetes (T1D), we show that treatment with auto-antigens modified with NAc-glucosamine-containing polymers prevents CD4⁺ T cell-mediated diabetes, expanded antigen-specific Tregs, and imbued lasting tolerance to subsequent challenge with activated diabetogenic T cells. These results demonstrate the efficacy of a clinically-viable tolerance-inducing therapy.