Genomic disruption of interferon receptors in NOD mice results in autoimmune diabetes with loss of adaptive tolerance

Background

Inflammatory cytokines, particularly the interferons, have been implicated in the pathogenesis of type 1 diabetes (T1D). Interferon-stimulated genes, including those that encode MHC proteins, are pathological hallmarks of the pancreatic islet during the development of T1D in both humans and the non-obese diabetic (NOD) mouse model. Further, many studies have shown that interferons promote the destructive interaction between antigen-specific CD8+ T cells and the beta cell. Surprisingly, deficiency of individual interferons or their receptors in NOD mice does not protect against the development of T1D, possibly due to signaling redundancy amongst the three receptors for type I, II and III interferons.

Methods

We used CRISPR/Cas9 mutagenesis to generate NOD mice that lack in all three interferon receptors (Ifnar1, Ifngr1 and Ifnlr1).

Results

Remarkably, while development of insulitis in the triple interferon receptor knockout NOD mice was delayed, mice developed diabetes with the same frequency as wild-type NOD mice. This result indicated that the lack of protection observed in triple knockout NOD mice was not due to functional redundancy between the three receptors. The frequency of islet specific autoreactive T cells was increased in these mice. Furthermore, they did not express PD-L1 on beta cells, and were resistant to diabetes acceleration by anti-PD-L1 antibody treatment, suggesting that normal interferon regulatory pathways were inhibited in these mice.

Conclusions

Collectively, these results indicate that in addition to the proinflammatory role of interferons they also are important for ‘adaptive tolerance’ that limits the action of pathogenic T cells. Hence, we observed a ‘neutral’ effect on progression of diabetes in NOD mice lacking interferon receptors. Loss of interferon-dependent adaptive tolerance appears to explain the lack of effect of interferon neutralisation on diabetes frequency.