Autoimmunity, allergy, and drug hypersensitivity are largely facilitated by undesirable T cell responses against inappropriate protein antigen targets. The continued rise in such immune disorders accelerates the need for innovative approaches capable of efficiently inducing robust antigen-specific T cell tolerance. Our lab has established strategies for co-opting endogenous immune surveillance networks for prophylactic tolerance induction, involving deletion, suppression, and regulatory T cell programming. Here, I advance the evaluation of these strategies for use in therapeutic settings, after T cell immunity has been established. First, using a carbohydrate polymer (pGlu) that targets antigen to hepatic APCs, I demonstrate induction of therapeutic T cell tolerance in proof-of-principle antigen models, as well as curative efficacy in a murine model of relapsing-remitting multiple sclerosis. Second, I explore a novel soluble apoptotic mediator (MFGE8) using in vitro and in vivo assays for its capacity to direct protein antigen into tolerogenic immune surveillance machinery. Through cellular and molecular-based investigations with the model antigen ovalbumin, along with a murine model of autoimmune disease, we demonstrate improvements with our engineered approaches against the unmodified protein antigens. Signatures of peripheral tolerance induction are revealed to rely on co-inhibitory ligand interaction such as PD-1. This thesis aims to further the development of two novel immunotherapies, as well as help elucidate the molecular mechanisms responsible for their effects.