APC-targeted proinsulin expression inactivates insulin-specific memory CD8+ T cells in NOD mice

Reeves, Peta LS, Rudraraju, Rajeev, Liu, Xiao, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845, Hamilton-Williams, Emma E and Steptoe, Raymond J 2017. APC-targeted proinsulin expression inactivates insulin-specific memory CD8+ T cells in NOD mice. Immunology and Cell Biology 95 (9) , pp. 765-774. 10.1038/icb.2017.48

Preview

PDF - Submitted Pre-Print Version Download (3MB) | Preview

Abstract

Type 1 diabetes (T1D) results from T-cell-mediated autoimmune destruction of pancreatic β cells. Effector T-cell responses emerge early in disease development and expand as disease progresses. Following β-cell destruction, a long-lived T-cell memory is generated that represents a barrier to islet transplantation and other cellular insulin-replacement therapies. Development of effective immunotherapies that control or ablate β-cell destructive effector and memory T-cell responses has the potential to prevent disease progression and recurrence. Targeting antigen expression to antigen-presenting cells inactivates cognate CD8+ effector and memory T-cell responses and has therapeutic potential. Here we investigated this in the context of insulin-specific responses in the non-obese diabetic mouse where genetic immune tolerance defects could impact on therapeutic tolerance induction. Insulin-specific CD8+ memory T cells transferred to mice expressing proinsulin in antigen-presenting cells proliferated in response to transgenically expressed proinsulin and the majority were rapidly deleted. A small proportion of transferred insulin-specific Tmem remained undeleted and these were antigen-unresponsive, exhibited reduced T cell receptor (TCR) expression and H-2Kd/insB15-23 tetramer binding and expressed co-inhibitory molecules. Expression of proinsulin in antigen-presenting cells also abolished the diabetogenic capacity of CD8+ effector T cells. Therefore, destructive insulin-specific CD8+ T cells are effectively inactivated by enforced proinsulin expression despite tolerance defects that exist in diabetes-prone NOD mice. These findings have important implications in developing immunotherapeutic approaches to T1D and other T-cell-mediated autoimmune diseases.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	0818-9641
Funders:	MRC
Date of Acceptance:	7 June 2017
Last Modified:	07 Nov 2023 01:03
URI:	https://orca.cardiff.ac.uk/id/eprint/105269

Citation Data

Cited 1 time in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item