Abstract
Recent advances in our understanding of immune tolerance, particularly the role of immune checkpoints in peripheral tolerance, have opened promising new avenues for therapeutic interventions in immune-related disorders. In this study, we developed a novel class of tolerogenic vaccines based on recombinant virus-like particles (tVLPs), engineered to display the immune checkpoint molecule CTLA-4 on their surface and incorporate specific antigens. These tVLPs promote the differentiation of tolerogenic dendritic cells (DCs) in vitro, characterized by a distinct functional phenotype and associated transcriptomic alterations. Furthermore, tVLPs inhibit DC activation and specifically modulate the antigen-specific T cell compartment, inducing a hyporesponsive state in effector T cells while promoting the activation of regulatory T cells (Tregs). The therapeutic efficacy of tVLPs was demonstrated in a murine model of food allergy, where five consecutive daily injections conferred protection against allergic symptoms and anaphylactic shock. Importantly, this effect was antigen-specific, long-lasting, and dependent on Tregs, as evidenced by the transfer of protection to naïve mice following adoptive transfer of Tregs from vaccinated animals. These findings establish tVLPs as a promising platform for the development of targeted immunotherapies for allergies and autoimmune diseases.