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

Reeves, P.L.S., Rudraraju, R., Wong, Florence ORCID: https://orcid.org/0000-0002-2812-8845, Hamilton-Williams, E.E. and Steptoe, R.J. 2017. Antigen presenting cell-targeted proinsulin expression converts insulin-specific CD8(+) T-cell priming to tolerance in autoimmune-prone NOD mice. European Journal of Immunology 47 (9) , pp. 1550-1561. 10.1002/eji.201747089

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Abstract

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. This article is protected by copyright. All rights reserved.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	APC; Autoimmunity; CD8+ T cell; Gene therapy; Insulin; NOD mice; Tolerance
Publisher:	John Wiley & Sons
ISSN:	0014-2980
Date of First Compliant Deposit:	10 July 2017
Date of Acceptance:	23 June 2017
Last Modified:	02 Nov 2022 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/102218

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