Tolerogenic IL-10-engineered dendritic cell-based therapy to restore antigen-specific tolerance in T cell mediated diseases.

Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cell responses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficiently generate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding for immunodominant antigen-derived peptides and IL-10. These transduced dendritic cells (designated DC) secrete IL-10 and efficiently downregulate antigen-specific CD4 and CD8 T cell responses from healthy subjects and celiac disease patients in vitro. In addition, DC induce antigen-specific CD49bLAG-3 T cells, which display the T regulatory type 1 (Tr1) cell gene signature. Administration of DC resulted in the induction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in pre-clinical disease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetes development. Collectively these data indicate that DC represent a platform to induce stable antigen-specific tolerance to control T-cell mediated diseases.