Characterizing the Immune Landscape in a Model for Early-Stage Type 1 Diabetes

Introduction: Pancreatic beta-cells, located in the islets of Langerhans, produce insulin, a hormone crucial for maintaining blood glucose homeostasis. Type I diabetes (T1D) is an autoimmune disease characterized by autoreactive T-cell-mediated destruction of beta-cells, leading to chronic hyperglycemia. While an antiviral type-I interferon (IFN-I) response to double-stranded RNA (dsRNA) has been implicated in early type I diabetes (T1D), evidence for causal viruses is limited. An alternative mechanism for the activation of interferon responses in beta-cells could involve endogenous dsRNA. Such dsRNA is typically dismantled by the RNA editing enzyme ADAR to prevent undue antiviral responses. Deficient RNA editing, therefore, may drive cellular IFN-I responses in the absence of viral infection. Supporting this, a recent genetic study has linked reduced RNA editing to autoimmune diseases, including T1D. Consistently, we have shown that ADAR inactivation in mouse beta-cells (beta-AdarKO) triggers IFN-I responses, causing insulitis, targeted beta-cell destruction, and diabetes, resembling early-stage T1D (Knebel et al., Cell Metabolism, 2024).

Materials and Methods: To characterize insulitis, we used immunohistochemistry and spatial proteomics. Insulin autoantibodies (IAA) in mouse serum were measured by ELISA. To determine the role of adaptive immunity, we combined beta-cell Adar deficiency with T-cell immunodepletion, RAG1 deficiency (lacking T- and B-cells), or PD-1 checkpoint blockade.

Results and Discussion: Insulitis predominantly consisted of macrophages/dendritic cells, with fewer T- and B-cells and no neutrophils.

insulin autoantibodies (IAA) were absent, and Granzyme B, a marker of cytotoxic cells, was sparse in inflamed islets and did not colocalize with cytotoxic T-cells, indicating that T- and B-cells likely act as bystanders.

Neither immune or genetic depletion of T- and B-cells prevented insulitis or diabetes, while PD-1 blockade increased diabetes incidence.

Conclusion: Adaptive immunity is not necessary for islet inflammation, selective beta-cell destruction or diabetes in beta-AdarKO mice. The increased diabetes incidence following PD-1 checkpoint blockade may represent a novel model for checkpoint diabetes and suggests that upon activation, T-cells might contribute to the disease.

Future research will explore the role of innate immunity in insulitis and diabetes development, providing insights into the immune-beta-cell interactions that characterize early stage T1D.