Although intensively being researched for decades, the precise etiological events triggering the autoimmune processes leading to beta cell death in type I diabetes (T1D) are largely unknown. Results from genome-wide association studies (GWAS) and sero-epidemiological studies have associated virus infections, and in particular infections with human enteroviruses such as coxsackievirus B4 (CVB4), with an increased risk of T1D. However, recognition and control of CVB4 infections by the host immune system remain poorly understood.
Here we demonstrate qualitative and quantitative differences in the Th1-mediated immune response towards CVB4 amongst strains with a different propensity for developing type I diabetes (C57BL/6, SJL/JArc and NOD/Lt), showing a strong and early T cell dependent response in SJL/JArc and a germinal-center dominated immune response in NOD/Lt mice. Compared to T1D-resistant C57BL/6 mice, we observed an increased and prolonged infiltration of the pancreas in both susceptible strains, SJL/JArc and NOD/Lt, resulting in sustained inflammation after viral clearance.
Differential gene expression analyses by RNAseq revealed a strong type 1 IFN response in infected target beta cells of SJL/JArc mice relative to C57BL/6 mice. The transcription factors IRF3 and IRF7 have been described to co-ordinately regulate the type I IFN response in immune cells in response to viral stimuli. Interestingly, the response towards CVB4 was dominated by the IFR7 rather than the IRF3 pathway, suggesting a virus specific bias in the type 1 IFN signature.
Understanding the relationship between an enterovirus infection and the development of a chronic inflammatory response in the pancreas will be useful to understand why enterovirus infections are associated with chronic islet cell inflammation and autoimmunity in some individuals but not in others.