9343 Protection Against Type 1 Diabetes Development In Mice With 4E-BP2 Deletion

Abstract Disclosure: V. Pita Grisanti: None. F. Pecanha: None. R. Louzada: None. M. Blandino: None. C. Jaramillo: None. N. Arenas: None. A. Bayer: None. E. Bernal-Mizrachi: None. Type 1 diabetes is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells that acquire an effector inflammatory phenotype. 4E-BP1/2 proteins are translational repressors and downstream targets of mTORC1, a key regulator of metabolism. mTORC1 signaling disruption is implicated in human diseases including diabetes. Activation of 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, which induces β-cell expansion and proliferation and is crucial for the regulation of adaptive immunity. However, the involvement of 4E-BP2 in type 1 diabetes development has not been explored. Therefore, this study aimed to determine the role of 4E-BP2/eIF4E signaling in type 1 diabetes prevention by regulation of β-cell survival and immune modulation. To investigate the role of 4E-BP2/eIF4E axis in diabetes pathogenesis, we used the non-obese diabetic (NOD) mouse model as a type 1 diabetes model, and generated mice with global deletion of 4E-BP2 in the NOD background (4E-BP2KONOD). We assessed type 1 diabetes development, glucose homeostasis, pancreas morphometry and immune responses in male and female 4E-BP2KONOD and control NOD mice. We found that 4E-BP2KONOD exhibited reduced diabetes incidence in male but not female mice. Reduction in diabetes incidence in 4E-BP2KONOD male mice was associated with comparable degree of insulitis and β-cell proliferation, and with preserved β-cell mass compared to the control NOD mice. Glucose-stimulated insulin secretion of the islets, assessed in vitro by static incubation, was significantly higher in the 4E-BP2KONOD compared to the NOD control. Autoimmune responses were also evaluated by assessment of insulitis and characterization of T cell compartments, which showed a decrease in splenic CD8+ cytotoxic T cells and an increase in pancreatic regulatory T cell (Treg) infiltration mainly by increased Treg survival in 4E-BP2KONOD mice compared to control NOD. Finally, adoptive transfer studies demonstrated that lymphocytes derived from male 4E-BP2KONOD mice were less diabetogenic than those derived from control NOD mice. In conclusion, this study showed that activation of 4E-BP2/eIF4E axis in 4E-BP2KONOD male mice protects against type 1 diabetes development by dampening autoimmune responses and preserving β-cell mass. Targeting 4E-BP2 may provide a potential treatment for type 1 diabetes. Presentation: 6/1/2024