<b>Protection Against Type 1 Diabetes Development in Mice with 4E-BP2 Deletion</b>

<p dir="ltr">Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. 4E-BP1/2 proteins are translational repressors and downstream targets of mTORC1. Activation of 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the non-obese diabetic (NOD) mouse model of T1D, and generated mice with global 4E-BP2 deletion in the NOD background (<i>Eif4epb2</i>^<em>-/-</em>). We assessed T1D development, glucose homeostasis, pancreas morphometry and immune responses in <i>Eif4epb2</i>^{<em>-/- </em>}and littermate control mice. We found that <i>Eif4epb2</i>^<em>-/-</em> male mice exhibited reduced diabetes incidence, which did not occur in female mice, and was associated with preserved β-cell mass, improved insulin secretion <i>in vitro</i>, and comparable insulitis. Characterization of T cell compartments showed decreased splenic CD8⁺ cytotoxic T cell proliferation and increased pancreatic regulatory T cell infiltration in <i>Eif4epb2</i>^<em>-/-</em> mice, potentially due to increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that <i>Eif4epb2</i>^<em>-/-</em> male lymphocytes were less diabetogenic than controls. Overall, activation of<b> </b>4E-BP2/eIF4E by 4E-BP2 deletion protects against T1D, identifying 4E-BP2 as a potential therapy target.</p>