| First Author | Reeves PLS | Year | 2017 |
| Journal | Eur J Immunol | Volume | 47 |
| Issue | 9 | Pages | 1550-1561 |
| PubMed ID | 28665492 | Mgi Jnum | J:249667 |
| Mgi Id | MGI:5924075 | Doi | 10.1002/eji.201747089 |
| Citation | Reeves PLS, et al. (2017) Antigen presenting cell-targeted proinsulin expression converts insulin-specific CD8+ T-cell priming to tolerance in autoimmune-prone NOD mice. Eur J Immunol 47(9):1550-1561 |
| abstractText | Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic beta 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. |
