4 years ago

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

Antigen presenting cell-targeted proinsulin expression converts insulin-specific CD8+ T-cell priming to tolerance in autoimmune-prone NOD mice
Emma E. Hamilton-Williams, Raymond J. Steptoe, Rajeev Rudraraju, Peta L. S. Reeves, F. Susan Wong
Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β 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. Therapies are required to overcome the T-cell responses that underlie type 1 diabetes. Transgenic expression of proinsulin in antigen-presenting cells induces tolerance in naïve insulin-specific CD8+ T cells through mechanisms that TCR downregulation and, potentially, expression of co-inhibitory molecules. In contrast in non-Tg mice insulin-specific CD8+ T cells appeared to undergo effector differentiation in pancreatic lymph nodes.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/eji.201747089

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