Type 1 diabetes is a chronic autoimmune disease, characterized by the immune-mediated destruction of insulin-producing b 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 À/À 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 À/À 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 À/À rats compared with KRV-infected WT rats; splenic regulatory T cells were diminished in WT but not Ifnar1 À/À rats. In contrast, splenic neutrophils were increased in KRV-infected Ifnar1 À/À 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 À/À 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.
Identifying the early islet cellular processes of autoimmune type 1 diabetes (T1D) in humans is challenging given the absence of symptoms during this period and the inaccessibility of the pancreas for sampling. Here, we study temporal events in pancreatic islets in LEW.1WR1 rats, in which autoimmune diabetes can be induced with virus infection, by performing transcriptional analysis of islets harvested during the pre-diabetic period. Single-cell RNA-Seq and differential expression analyses of islets from pre-diabetic rats reveal subsets of β and α cells under stress as evidenced by heightened expression, over time, of a transcriptional signature characterized by interferon-stimulated genes, chemokines including Cxcl10, major histocompatibility class I, and genes for the ubiquitin-proteasome system. Mononuclear phagocytes show increased expression of inflammatory markers. RNA-in situ hybridization of rat pancreatic tissue defines the spatial distribution of Cxcl10+ β and α cells and their association with CD8+ T cell infiltration, a hallmark of insulitis and islet destruction. Our studies define early islet transcriptional events during immune cell recruitment to islets and reveal spatial associations between stressed β and α cells and immune cells. Insights into such early processes can assist in the development of therapeutic and prevention strategies for T1D.
<p>Identifying the early islet cellular processes of autoimmune type 1 diabetes (T1D) in humans is challenging given the absence of symptoms during this period and the inaccessibility of the pancreas for sampling. Here, we study temporal events in pancreatic islets in LEW.1WR1 rats, in which autoimmune diabetes can be induced with virus infection, by performing transcriptional analysis of islets harvested during the pre-diabetic period. Single-cell RNA-Seq and differential expression analyses of islets from pre-diabetic rats reveal subsets of β and a cells under stress as evidenced by heightened expression, over time, of a transcriptional signature characterized by interferon-stimulated genes, chemokines including <em>Cxcl10</em>, major histocompatibility class I, and genes for the ubiquitin-proteasome system. Mononuclear phagocytes show increased expression of inflammatory markers. RNA-<em>in situ</em> hybridization of rat pancreatic tissue defines the spatial distribution of <em>Cxcl10</em>+ β and a cells and their association with CD8+ T cell infiltration, a hallmark of insulitis and islet destruction. Our studies define early islet transcriptional events during immune cell recruitment to islets and reveal spatial associations between stressed β and a cells and immune cells. Insights into such early processes can assist in the development of therapeutic and prevention strategies for T1D.</p>
<p>Identifying the early islet cellular processes of autoimmune type 1 diabetes (T1D) in humans is challenging given the absence of symptoms during this period and the inaccessibility of the pancreas for sampling. Here, we study temporal events in pancreatic islets in LEW.1WR1 rats, in which autoimmune diabetes can be induced with virus infection, by performing transcriptional analysis of islets harvested during the pre-diabetic period. Single-cell RNA-Seq and differential expression analyses of islets from pre-diabetic rats reveal subsets of β and a cells under stress as evidenced by heightened expression, over time, of a transcriptional signature characterized by interferon-stimulated genes, chemokines including <em>Cxcl10</em>, major histocompatibility class I, and genes for the ubiquitin-proteasome system. Mononuclear phagocytes show increased expression of inflammatory markers. RNA-<em>in situ</em> hybridization of rat pancreatic tissue defines the spatial distribution of <em>Cxcl10</em>+ β and a cells and their association with CD8+ T cell infiltration, a hallmark of insulitis and islet destruction. Our studies define early islet transcriptional events during immune cell recruitment to islets and reveal spatial associations between stressed β and a cells and immune cells. Insights into such early processes can assist in the development of therapeutic and prevention strategies for T1D.</p>
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