Mechanisms of Igf2 inhibition in thymic epithelial cells infected by coxsackievirus CV-B4

Epidemiological studies have evidenced a link between type 1 diabetes (T1D) and infections by enteroviruses, especially with coxsackievirus B4 (CV-B4). CV-B4 is able to infect human and murine thymic epithelial cells (TECs) and, in a murine TEC line, we have shown that the diabetogenic strain CV-B4 E2 decreases transcription of insulin-like growth factor 2 gene (Igf2), coding for the self-peptide of the insulin family. Here we show that in CV-B4 infection of mice alters Igf2 transcripts isoforms in TECs, followed by a decrease of pro-IGF2 precursor in the thymus. CV-B4 infection of a murine TEC line decreases Igf2 P3 promoter activity by targeting the region -68 to -22 upstream of the transcription start site (TSS) whereas Igf2 transcripts stability is not affected, pointing towards a regulation of Igf2 transcription. Our data also show that CV-B4 decreases IL-6/STAT3 signaling in vitro. This study provides new knowledge about the regulation of intrathymic Igf2 transcription by CV-B4 and reinforces the hypothesis that CV-B4 infection of the thymus could break central self-tolerance of the insulin family by decreasing Igf2 transcription and IGF2 presentation in thymus epithelium.