Antigen-specific nanoparticle tolerance treatment actively induces regulatory mechanisms via the STING pathway

Abstract

Abstract Antigen (Ag)-specific T cells are the underlying cause of many autoimmune diseases. T cells found at the site of tissue destruction not only in the exacerbation of disease, but contribute to the release of additiotnal self-epitopes resulting in the activation of spread eptitope-specific T cell populations perpetuating disease. Treatment with Ag-containingbiodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles, i.e. tolerogenic immune-modifying particles (TIMP), has been shown to be both safe and induces Ag-specific tolerance in mouse models of autoimmunity and allergy, as well as in a celiac disease Phase I/IIa clinical trial. We are in the process of assessing if the mechanism of action between Ag-specific TIMP treatment and Ag-coupled cell treatment, to thereby identify self-tolerance mechanisms in common between the two highly efficacious therapies. The PLP 139-151TCR transgenic model system was utilized to determine the cellular and molecular mechanisms driving Ag-specific tolerance mediated by tolerogenic nanoparticle treatment. These data show Ag-specific TIMP treatment induced both FoxP3 +iTregs and IL-10 +Tr1 regulatory in both naïve mice and mice pre-primed with Ag/CFA. Additionally, the expression of STING is required for the induction of tolerance. The involvement of the STING pathway for both TIMP and Ag-coupled cell treatment was confirmed in MOG 35-55EAE. The data also show that Ag-specific tolerance induction requires both Type I IFNs and PD-1/PD-L1 expression, which are downstream of STING activation and signaling. Treatment thus activates various Ag-specific Treg subsets capable of regulating responses to disease-relevant autoepitopes via a STING/IFNAR/PD-1/PD-L1 pathway.