Abstract 1.25 million Americans have type 1 diabetes (T1D), where the immune system destroys insulin- producing beta cells. Transplantation of islets into patients with type 1 diabetes as a curative measure has yet to overcome the barrier of immune-mediated destruction of the transplanted cells. Islet transplantation requires a drug regiment to suppress the immune response from allorejection, resulting in chronic immunosuppression with its own severe complications. Thus, targeted immunotherapy to prevent immune- mediated attack on transplanted islets without systemic immunosuppression would be ideal. Immunotherapies to date have targeted the adaptive immune response (T and B cells), ignoring the innate immune system (neutrophils, monocytes and macrophages). Siglecs are a family of sialic acid binding proteins, each with a preference for a particular type of sialic acid moiety on the cell surface. Siglec-E is an inhibitory receptor expressed on neutrophils, monocytes and macrophages that functions to block inflammation. Therefore, engagement of Siglec-E by innate immune cells could promote immune tolerance rather than inflammation and immune activation, which may be a novel approach to treat T1D. We have demonstrated that the sialyltransferase ST8Sia6 generates α2,8 linked disialic acids on O-linked glycoproteins which are recognized specifically by Siglec-E. ST8Sia6 knockout mice have decreased recombinant Siglec-E binding to T cells. We hypothesized that expression of ST8Sia6 could inhibit the immune response by generating ligands for Siglec-E on the cell surface. To test this, we generated a novel line of mice in our laboratory where ST8Sia6 is constitutively overexpressed only in pancreatic β cells (“RIP- cre LNL-tTA ST8Sia6”). RIP-cre LNL-tTA ST8Sia6 mice are healthy, have resting blood glucose levels indistinguishable from littermate controls, and respond normally to a glucose tolerance test. Therefore, constitutive expression of ST8Sia6 in pancreatic β cells does not interfere with β cell function or survival. To test whether constitutive ST8Sia6 expression could be protective, we utilized the multiple low dose streptozocin (STZ) model to induce diabetes, which has a strong pro-inflammatory component. We demonstrated that targeted expression of ST8Sia6 in pancreatic β cells provided protection from diabetes induced using MLD-STZ. The median onset to diabetes was 28 days for ST8Sia6-expressing mice as compared to 18.5 days for littermate controls. In addition, the hyperglycemia was less severe in ST8Sia6- expressing mice. Thus, ST8Sia6 expression provides protection in the MLD-STZ model of diabetes. The focus of this proposal is to target ST8Sia6 expression in β cells in autoimmune models to show protection from immune-mediated attack.