Antigen-specific messenger RNA lipid nanoparticle therapy with mTOR inhibition promotes regulatory T cells and limits allergy.

Abstract

Immune tolerance in allergic diseases is associated with attenuation of T_H2 responses by shifting of antigen-specific immunity toward T_H1 and regulatory T-cell pathways, but current strategies incompletely induce durable regulatory immunity. We determined whether combining an allergen-encoded messenger RNA (mRNA) lipid nanoparticle (LNP) vaccine with inhibition of the mechanistic target of rapamycin (mTOR) enhances regulatory T-cell responses. Mice were immunized with an allergen-encoded mRNA-LNP vaccine alone or in combination with an mTOR inhibitor, followed by induction of a preclinical model of allergic asthma. Antigen-specific T-cell responses, eosinophil activation, airway hyperresponsiveness, mucus production, and markers of cytotoxicity were assessed. Immunization with allergen-encoded mRNA-LNP elicited T_H1-associated and cytotoxic CD8⁺ T responses that counterbalanced T_H2 immunity. Coadministration with an mTOR inhibitor shifted this profile by promoting generation of functional regulatory T cells and attenuating IFN-γ production and CD8⁺ T-cell responses. This combinatorial strategy preserved the antiallergic effects of mRNA-LNP immunization, reduced eosinophil activation markers, and limited vaccine-associated cytotoxicity. The ability of an mTOR inhibitor to profoundly modify mRNA-LNP therapy by inducing regulatory T cells presents a potential strategy to enhance regulatory immunity in the treatment of allergy and other inflammatory diseases.