An Early Islet Transcriptional Signature Is Associated With Local Inflammation in Autoimmune Diabetes

Abstract

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.

Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis

“…IFN-γ is important for homing of autoreactive CD8 + T cells into islets by upregulating expression of chemokine receptors on CD8 + T cells, including effector-associated CXCR3, and its ligands, such as CXCL10, on ß cells ( Christen and Kimmel, 2020 ). Islets display a strong IFN-regulated gene signature at the time of immune cell infiltration, including upregulation of Cxcl10 , Cxcl9 and Cxcl11 ( Calderon et al, 2011 ; Derr et al, 2023 ). Blocking CXCL10 reduces diabetes ( Christen et al, 2003 ; Christen and Kimmel, 2020 ) and splenocytes from diabetic NOD mice were less efficient at transferring diabetes into IFN-γ or IFNGR-deficient NOD mice due to impaired homing of T cells into islets ( Savinov et al, 2001 ).…”