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

• Published in: European journal of immunology Vol. 47; no. 9; pp. 1550 - 1561
• Main Authors: Reeves, Peta L. S., Rudraraju, Rajeev, Wong, F. Susan, Hamilton‐Williams, Emma E., Steptoe, Raymond J.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.09.2017
• Subjects: Animals; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Antigens; APC; Autoantigens - immunology; Autoimmune diseases; Autoimmunity; Beta cells; CD8 antigen; CD8+ T cell; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Defects; Diabetes mellitus; Diabetes Mellitus, Type 1 - immunology; Gene therapy; Humans; Immune Tolerance; Immunological tolerance; Insulin; Islets of Langerhans - immunology; Lymph nodes; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred NOD; NOD mice; Pancreas; Proinsulin - immunology; Rodents; T cell receptors; Tolerance; Autoimmunity; APC; Tolerance; Gene therapy; NOD mice; CD8+ T cell; Insulin
• DOI: 10.1002/eji.201747089
• ISSN: 0014-2980

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.