Beta Cell Heterogeneity in the Acute Interferon Alpha Response
type: CreativeWork
description: Type 1 diabetes (T1D) is characterized by autoimmune destruction of the insulin-producing β-cells in the pancreatic islet. This autoimmunity is hypothesized to result from a combination of genetic and environmental factors, with early childhood viral infection being a leading hypothesis for the latter. In response to viral infections, the innate immune system produces various cytokines, including interferon alpha (IFN-α), which has long been implicated in T1D pathogenesis. Our study explores how IFN-α influences human β-cell function, particularly its role in reactive oxygen species (ROS) production—signaling molecules essential for normal β-cell function but detrimental in excess. Using intravital microscopy and a β-cell-specific ROS biosensor, we identified a subset of β-cells that rapidly produce ROS in response to IFN-α. Interestingly, phenotyping data from the donors indicated that healthier β-cells were more likely to exhibit this response. In vitro experiments confirmed that IFN-α drives mitochondrial superoxide production in a subset human of β-cells, prompting us to investigate the molecular basis of this phenomenon. RNA sequencing of sorted IFN-α–treated cells revealed an upregulation of immune-related genes, and comparison with single-cell datasets showed that these genes are more highly expressed in β-cells from healthy individuals than those with T1D. These findings suggest that IFN-α–induced ROS production may be a marker of β-cell resilience, highlighting differences in how β-cells respond to stress. Understanding this mechanism could offer new insights into why some β-cells are more vulnerable in T1D and potentially point to novel strategies for preserving β-cell function in diabetes. While our investigation into IFN-α signaling revealed how immune cytokines influence β-cell physiology, we also sought to explore immune landscape changes during disease progression. Using the Akoya Phenocycler, we mapped immune cell populations in the pancreata of huma…
abstract: Type 1 diabetes (T1D) is characterized by autoimmune destruction of the insulin-producing β-cells in the pancreatic islet. This autoimmunity is hypothesized to result from a combination of genetic and environmental factors, with early childhood viral infection being a leading hypothesis for the latter. In response to viral infections, the innate immune system produces various cytokines, including interferon alpha (IFN-α), which has long been implicated in T1D pathogenesis. Our study explores how IFN-α influences human β-cell function, particularly its role in reactive oxygen species (ROS) production—signaling molecules essential for normal β-cell function but detrimental in excess. Using intravital microscopy and a β-cell-specific ROS biosensor, we identified a subset of β-cells that rapidly produce ROS in response to IFN-α. Interestingly, phenotyping data from the donors indicated that healthier β-cells were more likely to exhibit this response. In vitro experiments confirmed that IFN-α drives mitochondrial superoxide production in a subset human of β-cells, prompting us to investigate the molecular basis of this phenomenon. RNA sequencing of sorted IFN-α–treated cells revealed an upregulation of immune-related genes, and comparison with single-cell datasets showed that these genes are more highly expressed in β-cells from healthy individuals than those with T1D. These findings suggest that IFN-α–induced ROS production may be a marker of β-cell resilience, highlighting differences in how β-cells respond to stress. Understanding this mechanism could offer new insights into why some β-cells are more vulnerable in T1D and potentially point to novel strategies for preserving β-cell function in diabetes. While our investigation into IFN-α signaling revealed how immune cytokines influence β-cell physiology, we also sought to explore immune landscape changes during disease progression. Using the Akoya Phenocycler, we mapped immune cell populations in the pancreata of huma…
author: Wagner, Leslie Elaine
language: en_US
keywords: Beta-cell, Diabetes, Heterogeneity, Interferon, Microscopy
date published: 2025-06
date modified: 2026-07-24T02:40:24Z
provider: IUPUI
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: IUPUI

PropertyValue
property ID: Handle
value: https://hdl.handle.net/1805/49312

PropertyValue
property ID: DOI
value: 10.7912/97H0-3850