Type I IFN-Driven Immune Cell Dysregulation in Rat Autoimmune Diabetes
Derr, Alan G.
Trombly, Melanie I.
Wang, Jennifer P.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Program in Bioinformatics and Integrative Biology
Diabetes Center of Excellence
Department of Medicine
Document TypeJournal Article
Endocrine System Diseases
Endocrinology, Diabetes, and Metabolism
Immune System Diseases
Immunology and Infectious Disease
Nutritional and Metabolic Diseases
MetadataShow full item record
AbstractType 1 diabetes is a chronic autoimmune disease, characterized by the immune-mediated destruction of insulin-producing beta 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.
Qaisar N, Arowosegbe A, Derr AG, Kucukural A, Satish B, Racicot R, Guo Z, Trombly MI, Wang JP. Type I IFN-Driven Immune Cell Dysregulation in Rat Autoimmune Diabetes. Immunohorizons. 2021 Oct 26;5(10):855-869. doi: 10.4049/immunohorizons.2100088. PMID: 34702762. Link to article on publisher's site