Antigen presenting cell-targeted proinsulin expression converts insulin-specific CD8(+) T-cell priming to tolerance in autoimmune-prone NOD mice

作者：Reeves Peta L S; Rudraraju Rajeev; Wong F Susan; Hamilton Williams Emma E; Steptoe Raymond J^*

来源：European Journal of Immunology, 2017, 47(9): 1550-1561.

DOI：10.1002/eji.201747089

• APC
• Autoimmunity
• CD8(+) T cell
• Gene therapy
• Insulin
• NOD mice
• Tolerance

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8(+) T cells transferred to mice in which proinsulin was transgenically expressed in APCs underwent several rounds of division and the majority were deleted. Residual insulin-specific CD8(+) T cells were rendered unresponsive and this was associated with TCR downregulation, loss of tetramer binding and expression of a range of co-inhibitory molecules. Notably, accumulation and effector differentiation of insulin-specific CD8(+) T cells in pancreatic lymph nodes was prominent in non-transgenic recipients but blocked by transgenic proinsulin expression. This shift from T-cell priming to T-cell tolerance exemplifies the tolerogenic capacity of autoantigen expression by APC and the capacity to overcome genetic tolerance defects.

• 出版日期2017-9