The Santamaria lab has extensively studied the effects of a nanoparticle-based therapeutic approach for autoimmunity, involving the systemic administration of peptide/major histocompatibility complex (pMHC) class II-coated iron oxide nanoparticles (pMHCII-NPs). Therapeutic activity of pMHCII-NPs has been validated across a series of pre-clinical animal models of autoimmune disease. pMHCII-NP therapy targets pathogenic antigen-experienced auto-reactive T cells specific for an autoimmune disease-relevant epitope, resulting in proliferation and re-programming of these T cells into a suppressive subset that can blunt disease. Previous investigations on the pharmacodynamic, pharmacokinetic and therapeutic activities of pMHCII-NP have shown that the expanded population of cognate antigen-specific cells acquires a TR1 phenotype. Secretion of anti-inflammatory cytokines by these TR1 cells, as well as generation of additional downstream cellular effectors of immunoregulation have been previously implicated. However, the relative contribution and individual role of each of these mediators to the total therapeutic activity of pMHCII-NP remained unknown. To answer these questions, we dissected the pMHCII-NP-induced regulatory cell network using a genetic conditional knockout approach in the experimental autoimmune encephalomyelitis (EAE) model. We hypothesized that pMHCII-NPs treatment triggers the formation of a complex immunoregulatory cell pathway that involves multiple immune and possibly non-immune cell subsets that collectively contribute to the suppression of autoimmunity by inducing bystander immunoregulation and tissue repair. The results presented in this thesis have helped clarify multiple aspects of pMHCII-NP-induced immunoregulatory cell networks. We have delineated the main cellular sources of suppressive cytokines as well as some of their downstream cellular targets. In addition, we have described a novel subset of pMHCII-NP-cognate TR1 cells and its contribution to the therapeutic effect. Bystander suppression in a non-antigen-specific manner has also been described, and the mechanism by which pMHCII-NPs induce tissue repair has also been characterized. Collectively, these studies have further confirmed that pMHCII-NP’s therapeutic effect requires the formation of a complex antigen-specific regulatory cell network and identified the respective contribution of some of the molecular mediators involved in the suppression of inflammation. We have also proven that bystander immunoregulation can be achieved by targeting disease-irrelevant bacterial antigens and delineated a pMHCII-NP-induced active tissue repair mechanism.