Interferon Signaling in the T1D Islet Microenvironment

ABSTRACT Type 1 diabetes (T1D) is characterized by a complex interplay among various cellular constituents within the islet microenvironment, including immune cells, endocrine cells, endothelial cells, and acinar cells. Our team has previously advanced the understanding of stress-responsive signaling cascades within β cells, revealing their role in triggering or exacerbating autoimmunity. Building on these findings, this renewal HIRN application aims to identify pivotal intracellular signaling pathways and develop targeted interventions to modulate early disease processes that shape human islet biology in T1D. Our approach aligns with the objectives of RFA-DK- 23-007, leveraging a synergistic Team Science framework to explore interferon signaling in β cells. Interferons, released by islet-invading immune cells, play a crucial role in T1D. Genes related to interferon response (PTPN2, IFIH1, TYK2) are linked to T1D susceptibility. While the acute β cell response to interferons is adaptive, a sustained response in genetically susceptible individuals may initiate or propagate insulitis, leading to T1D. Our data indicate that an interferon transcriptional signature is present early in T1D, with IFN-α influencing β cells initially, followed by IFN-γ during advanced insulitis. Additionally, post-transcriptional mechanisms, including mRNA translation and posttranslational modifications (particularly S-palmitoylation), finely tune interferon responses to balance pro- and anti-T1D effects. We hypothesize that the interferon response in β cells is a critical early cellular cascade, balancing β cell survival and autoimmune susceptibility in T1D. We will test this hypothesis through the following aims: Aim 1: Define the impact of post-translational S-palmitoylation on interferon signaling in β cells. Aim 2: Define the contribution of mRNA translation to the interferon response in β cells. Aim 3: Investigate the regulatory mechanisms of interferon signaling on β cell PD-L1 production. With the demonstration that T1D onset can be delayed in humans, there is a compelling need to identify stress response pathways in β cells as potential targets for disease prevention. This HIRN proposal builds on a successful prior HIRN team collaboration, employs innovative methods to investigate interferon responses in human β cells, and promises to provide new insights into manipulating this early signaling pathway to modify T1D progression.