Antigen specific tolerance and the prevention of autoimmune type 1 diabetes occurs through indirect antigen presentation and requires programmed death ligand 1 (THER5P.918)

Antigen-coupled ethylene carbodiimide-fixed cells is an attractive therapeutic platform for treating human patients with type 1 diabetes since these cells can prevent and reverse diabetes in the non-obese diabetic mouse model of diabetes. However, the mechanisms contributing to the induction of T cell tolerance in vivo following treatment are unclear. Therefore, we used the BDC2.5 T cell transfer model to study how p31-coupled cells inhibit T cell function in vivo. Our results demonstrate that indirect antigen presentation was critical for tolerance induction in vivo. We further demonstrate that PD-L1 on the host antigen presenting cells is required for tolerance induction. Importantly, using two-photon microscopy we show that BDC2.5 T cells arrest on CD11c+ dendritic cells during the induction of tolerance, suggesting that these cells are responsible for presenting coupled cell antigen and tolerance induction. To increase the feasibility of translating antigen coupled cells to the clinic, we demonstrate that whole blood preparations and frozen cells are sufficient for tolerance induction, a significant concern for donor coupled cell sources when considering translation to human patients. These data further our understanding of how antigen-coupled cells induce tolerance and how this tolerance protocol could be altered to increase clinical feasibility.