Tolerance Induced by Antigen-Loaded PLG Nanoparticles Affects the Phenotype and Trafficking of Transgenic CD4+ and CD8+ T Cells

We have shown that PLG nanoparticles loaded with peptide antigen can reduce disease in animal models of autoimmunity and in a phase 1/2a clinical trial in celiac patients. Clarifying the mechanisms by which antigen-loaded nanoparticles establish tolerance is key to further adapting them to clinical use. The mechanisms underlying tolerance induction include the expansion of antigen-specific CD4(+) regulatory T cells and sequestration of autoreactive cells in the spleen. In this study, we employed nanoparticles loaded with two model peptides, GP(33-41) (a CD8 T cell epitope derived from lymphocytic choriomeningitis virus) and OVA(323-339) (a CD4 T cell epitope derived from ovalbumin), to modulate the CD8(+) and CD4(+) T cells from two transgenic mouse strains, P14 and DO11.10, respectively. Firstly, it was found that the injection of P14 mice with particles bearing the MHC I-restricted GP(33-41) peptide resulted in the expansion of CD8(+) T cells with a regulatory cell phenotype. This correlated with reduced CD4(+) T cell viability in ex vivo co-cultures. Secondly, both nanoparticle types were able to sequester transgenic T cells in secondary lymphoid tissue. Flow cytometric analyses showed a reduction in the surface expression of chemokine receptors. Such an effect was more prominently observed in the CD4(+) cells rather than the CD8(+) cells.

Automated summary

This study demonstrated that PLG nanoparticles loaded with peptide antigen could mitigate diseases in animal models and celiac patients. The mechanisms of tolerance induction include the expansion of antigen-specific CD4(+) regulatory T cells and the sequestration of autoreactive cells in the spleen, which are crucial for clinical application. Additionally, nanoparticles were able to modulate CD8(+) and CD4(+) T cells in transgenic mouse strains, showing potential for future therapeutic development.