Antigen-specific suppression of previously activated T cell responses via polymeric GalNAc antigen conjugation

Abstract

Abstract Current treatments for autoimmunity, allergy, and drug hypersensitivity require continuous global immune suppression. Here we demonstrate in vivo therapeutic efficacy of antigen-specific T cell tolerance induction following prior immunization in various models of murine immunity. Our lab has engineered an N-acetylgalactosamine polymer (pGal) that can be conjugated to protein antigen and delivered intravenously to immunosuppressive hepatic antigen presenting cells, thereby inducing lasting immune regulation without off target effects. In this work, we show treatment with pGal-ovalbumin (OVA) conjugates can suppress previously activated T cells in an antigen-specific fashion. We describe the suppressive effects and underlying signatures of tolerogenic T cell reprogramming by comparing treatment with native OVA to pGal-OVA. Therapeutic treatment with pGal-OVA results in reduced T cell expansion and activation after secondary challenge, higher expression levels of suppressive/exhausted markers such as PD1 and TOX, and markedly lower production of cytokines including IFNg, TNFa, and IL-17 following in vitro restimulation with antigen. Further investigation of antigen-specific tolerance induction utilizing pGal-conjugates can lead to potentially curative approaches for controlling aberrant immunity to self or innocuous foreign protein.