Type I IFN-Driven Immune Cell Dysregulation in Rat Autoimmune Diabetes.
Type I IFN-Driven Immune Cell Dysregulation in Rat Autoimmune Diabetes.
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DOI：
10.4049/immunohorizons.2100088
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发表时间：
2021-10-26
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1型糖尿病是一种慢性自身免疫性疾病，其特征在于免疫介导的胰岛β细胞的破坏。先天免疫抗病毒反应的基本组成部分，包括I型IFN和IFN受体（IFNAR）介导的信号通路，可能有助于人类1型糖尿病易感性。我们先前表明，LEW.1WR1 Ifnar 1 −/−大鼠在Kilham大鼠病毒（KRV）感染后糖尿病发生率显著降低。为了描述IFNAR缺失对KRV诱导的糖尿病中免疫细胞群的影响，我们在病毒感染后但胰岛炎和糖尿病发作前对LEW.1WR1野生型（WT）和Ifnar 1 −/−大鼠的脾脏进行了流式细胞术分析。我们发现，与KRV感染的WT大鼠相比，KRV感染的LEW.1WR1 Ifnar 1 −/−大鼠的CD 8 + T细胞和NK细胞相对减少; WT大鼠的脾脏调节性T细胞减少，但Ifnar 1 −/−大鼠没有减少。相反，与KRV感染的WT大鼠相比，KRV感染的Ifnar 1 −/−大鼠的脾中性粒细胞增加。对KRV感染大鼠脾细胞的转录分析证实，与WT大鼠相比，Ifnar 1 −/−中IFN刺激的基因减少，并显示与中性粒细胞趋化性和MHC II类相关的转录物增加。单细胞RNA测序证实，MHC II类转录增加单核细胞和巨噬细胞，许多类型的脾细胞港口KRV。总的来说，这些发现确定了在自身免疫性糖尿病大鼠模型中IFNAR破坏后先天性和适应性免疫细胞的动态变化，为I型IFN在自身免疫中的作用提供了见解。
Type 1 diabetes is a chronic autoimmune disease, characterized by the immune-mediated destruction of insulin-producing β cells of pancreatic islets. Essential components of the innate immune antiviral response, including type I IFN and IFN receptor (IFNAR)–mediated signaling pathways, likely contribute to human type 1 diabetes susceptibility. We previously showed that LEW.1WR1 Ifnar1−/− rats have a significant reduction in diabetes frequency following Kilham rat virus (KRV) infection. To delineate the impact of IFNAR loss on immune cell populations in KRV-induced diabetes, we performed flow cytometric analysis in spleens from LEW.1WR1 wild-type (WT) and Ifnar1−/− rats after viral infection but before the onset of insulitis and diabetes. We found a relative decrease in CD8+ T cells and NK cells in KRV-infected LEW.1WR1 Ifnar1−/− rats compared with KRV-infected WT rats; splenic regulatory T cells were diminished in WT but not Ifnar1−/− rats. In contrast, splenic neutrophils were increased in KRV-infected Ifnar1−/− rats compared with KRV-infected WT rats. Transcriptional analysis of splenic cells from KRV-infected rats confirmed a reduction in IFN-stimulated genes in Ifnar1−/− compared with WT rats and revealed an increase in transcripts related to neutrophil chemotaxis and MHC class II. Single-cell RNA sequencing confirmed that MHC class II transcripts are increased in monocytes and macrophages and that numerous types of splenic cells harbor KRV. Collectively, these findings identify dynamic shifts in innate and adaptive immune cells following IFNAR disruption in a rat model of autoimmune diabetes, providing insights toward the role of type I IFNs in autoimmunity.