Our lab has been developing a nanoparticle-based therapy consisting of the administration of peptide/major histocompatibility complex (pMHC) class I-coated iron oxide nanoparticles (NPs). This therapy has proven to be successful in both preventing and reverting T1D. The studies carried out in our lab have allowed us to elucidate the nature of the protection afforded by this therapy. The administration of the peptide/MHC class I-coated NPs induced the expansion of low-avidity antigen-specific CD8+ T-cells with regulatory properties. In addition, evidence suggests that the treatment-expanded cells are derived from antigen-experienced precursors generated during the autoimmune process. The same treatment into a knock-in mouse that lacks the cognate epitope neither resulted in expansion nor was able to induce diabetes reversal.
Our findings with the MHC class I-coated nanoparticles urged us to ask whether the paradigm that applies for CD8+ T-cells could also apply for autorreactive CD4+ T-cells. That is, whether the autoimmune process leads autorreactive to the generation of CD4+ T-cells designed to become immune regulators in order to try to prevent further damage. Through their involvement as both effectors and regulators in most autoimmune and hypersensitivity disorders, CD4+ T-cells are, conceptually, as good (if not better) targets for immune modulation as CD8+ T-cells. To answer the above question, we followed the same approach used for the study of CD8+ T-cells. We hypothesized that pMHC class II-coated NPs would be equally effective in the expansion of CD4+ T-cells with regulatory properties. And, therefore, we expected the NP treatment to be able to blunt autoimmune progression.
The studies presented in this thesis support this hypothesis. Systemic administration of disease-relevant pMHCII-coated NPs blunted the autoimmune attack in a model of type 1 diabetes and experimental autoimmune encephalomyelitis. In both cases, this was mediated by the expansion of IL-10- and TGF-β1 producing CD4+ T-cells, with a surface and transcriptional phenotype identical to the so-called type 1 regulatory (Tr1) T-cells. In addition, we confirmed that the suppression of autoimmunity was mediated by IL-10 and TGF-β1 produced by these cells and the induction of several regulatory networks downstream of the Tr1 activation, such as the expansion of IL-10-producing Bregs and the suppression of cytokine production by CD11b+ myeloid antigen-presenting cells. Further characterization of the origin of the NP-expanded Tr1 cells led us to conclude that NPs selectively target Tr1 precursors contained in the cognate memory pool, with basal regulatory capability.
In summary, these studies conclude that chronic inflammation induces the generation of a memory pool of regulatory cell precursors in order to prevent further tissue damage. Furthermore, our pMHCII nanovaccine can induce the expansion/differentiation of these precursors in order to achieve a therapeutical balance between pathological and regulatory cells and blunt the autoimmune process.