Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

TLDR

Type 1 diabetes is a T‑cell–mediated autoimmune disease in which insulin is a key target, yet the precise mechanism of β‑cell destruction remains unknown. The authors identified the insulin B‑chain peptide insB10‑18, which binds HLA‑A2 with high affinity, is processed by proteasomes, transported by TAP1, and presented on the cell surface, and used it to prime PBMCs and isolate CD8 T cells that specifically recognize this peptide. Tetramer staining of insB10‑18 revealed that autoreactive CD8 T cells are strongly associated with recurrent autoimmunity and graft failure in islet transplant recipients, demonstrating their role in β‑cell destruction in humans.

Abstract

Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with β cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of β cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLA-A2 insB10-18 tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with β cell destruction in type 1 diabetes in humans.