Multipeptide-coupled nanoparticles induce tolerance in ‘humanised’ HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes

Xinyu Xu, Lingling Bian, Min Shen, Xin Li, Jing Zhu, Shuang Chen, Lei Xiao, Qingqing Zhang, Heng Chen, Kuanfeng Xu, Tao Yang

Induction of antigen-specific immunological tolerance may provide an attractive immunotherapy in the NOD mouse model but the conditions that lead to the successful translation to human type 1 diabetes are limited. In this study, we covalently linked 500 nm carboxylated polystyrene beads (PSB) with a mixture of immunodominant HLA-A*02:01-restricted epitopes (peptides-PSB) that may have high clinical relevance in humans as they promote immune tolerance; we then investigated the effect of the nanoparticle-peptide complexes on T cell tolerance. PSB-coupled mixtures of HLA-A*02:01-restricted epitopes were administered to HHD II mice via intravenous injection. The effects on delaying the course of the disease were verified in NOD.β2m (null) HHD mice. The diabetogenic HLA-A*02:01-restricted cytotoxic lymphocyte (CTL) responses to treatment with peptides-PSB were validated in individuals with type 1 diabetes. We showed that peptides-PSB could induce antigen-specific tolerance in HHD II mice. The protective immunological mechanisms were mediated through the function of CD4(+)CD25(+) regulatory T cells, suppressive T cell activation and T cell anergy. Furthermore, the peptides-PSB induced an activation and accumulation of regulatory T cells and CD11c(+) dendritic cells through a rapid production of CD169(+) macrophage-derived C-C motif chemokine 22 (CCL22). Peptides-PSB also prevented diabetes in 'humanised' NOD.β2m (null) HHD mice and suppressed pathogenic CTL responses in people with type 1 diabetes. Our findings demonstrate for the first time the potential for using multipeptide-PSB complexes to induce T cell tolerance and halt the autoimmune process. These findings represent a promising platform for an antigen-specific tolerance strategy in type 1 diabetes and highlight a mechanism through which metallophilic macrophages mediate the early cell-cell interactions required for peptides-PSB-induced immune tolerance.