Endogenous retrovirus (ERV) are remnants of ancient retroviruses that have been incorporated into the genome and evidence suggests that they may play a role in the etiology of T1D. We previously identified a murine leukemia retrovirus-like ERV whose Env and Gag antigens are involved in autoimmune responses in non-obese diabetic (NOD) mice. In this study, we show that the Gag antigen is present in the islet stromal cells. Although Gag gene transcripts were present, Gag protein was not detected in diabetes-resistant mice. Cloning and sequencing analysis of individual Gag genes revealed that NOD islets express Gag gene variants with complete open-reading frames (ORFs), in contrast to the diabetes-resistant mice, whose islet Gag gene transcripts are mostly non-ORFs. Importantly, the ORFs obtained from the NOD islets are extremely heterogenous, coding for various mutants that are absence in the genome. We further show that Gag antigens are stimulatory for autoreactive T cells and identified one islet-expressing Gag variant that contains an altered peptide ligand capable of inducing IFN-gamma release by the T cells. The data highlight a unique retrovirus-like factor in the islets of the NOD mouse strain, which may participate in key events triggering autoimmunity and T1D.

中文翻译：

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内源性逆转录病毒Gag抗原及其基因变异是在非肥胖糖尿病小鼠的胰岛中表达的独特自身抗原。

内源性逆转录病毒（ERV）是已整合到基因组中的古老逆转录病毒的残留物，证据表明它们可能在T1D的病因中起作用。我们先前确定了鼠白血病逆转录病毒样ERV，其Env和Gag抗原参与非肥胖糖尿病（NOD）小鼠的自身免疫反应。在这项研究中，我们表明Gag抗原存在于胰岛基质细胞中。尽管存在Gag基因转录本，但在抗糖尿病的小鼠中未检测到Gag蛋白。单个Gag基因的克隆和测序分析表明，与糖尿病抗性小鼠相比，NOD胰岛表达具有完整开放阅读框（ORF）的Gag基因变体，而抗糖尿病小鼠的胰岛Gag基因转录物大多是非ORF。重要的是，从NOD胰岛获得的ORF非常不均一，编码基因组中不存在的各种突变体。我们进一步表明，Gag抗原对自身反应性T细胞具有刺激性，并鉴定了一种表达胰岛的Gag变体，其中包含能够诱导T细胞释放IFN-γ的肽配体改变。数据突出显示了NOD小鼠品系的胰岛中独特的逆转录病毒样因子，该因子可能参与触发自身免疫和T1D的关键事件。