ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Investigating the role of interferon signalling in the CD8 T cell transgenic NOD8.3 model of type 1 diabetes (#229)

David J De George 1 , Gaurang Jhala 1 , Evan Pappas 1 , Tom Brodnicki 1 , Bala Krishnamurthy 1 , Thomas Kay 1 , Helen Thomas 1
  1. St Vincent's Institute, Fitzroy, VIC, Australia

Type 1 diabetes is an autoimmune disease involving T-cell autoreactivity against the insulin-producing β-cells of the pancreas, which results in dependence on exogenous insulin. Autoreactive CD8+ T-cells kill β-cells directly through MHC I-TCR interactions and perforin-granzyme release. Interferons, particularly interferon-γ, create an inflammatory pancreatic environment, regulate immune cell trafficking, and control β-cell antigen presentation to activated immune cells. Previous studies show that despite their role in these pathogenic processes, loss of interferon-γ or its receptor does not prevent diabetes in NOD mice.

In contrast, interferon receptor deficiency in the accelerated CD8+ T-cell transgenic NOD/8.3 model, in which over 90% of the CD8+ T-cells respond to the β-cell peptide IGRP206–214, results in significant protection from diabetes. Immunohistochemistry and flow cytometry shows delayed insulitis development and maintained β-cell mass despite aberrant T-cell expansion within the islets in NOD/8.3 mice lacking interferon receptors. This protection correlates with reduced MHC I expression on β-cells, dendritic cells, and inflammatory macrophages. The proportion of the latter population is decreased in the spleen and islets of interferon-receptor deficient NOD/8.3 mice, indicating an overall reduced ability to present β-cell antigens. Consequently, these mice have reduced proportions of CD44hi CD8+ T-cells in the spleen, indicating reduced antigen experience and increased expression of KLRG1 and PD-1 on antigen experienced CD8+ T-cells, suggestive of chronic antigen persistence.

Future work will use single cell RNA sequencing to determine how NOD mice, with a polyclonal T-cell repertoire, develop diabetes despite reduced antigen presentation due to interferon receptor deficiency. This research contributes to understanding pathogenic mechanisms in autoimmune diabetes, which is required to develop much-needed immunomodulatory therapies that prevent β-cell destruction.

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