Project summary: Type 1 diabetes affects millions of individuals globally, and is a significant cause of morbidity and mortality. The autoimmune process behind this disease is not fully understood, complicating attempts to prevent or cure it. Islet transplantation is a potentially curative approach, but remains hindered by numerous adverse complications, including lifelong immunosuppression required after the procedure. Thus, the objective of this grant is to investigate an immunomodulatory approach for mitigating autoimmunity, with the goals of better understanding the aberrant immune response in type 1 diabetes and contributing to an improved therapeutic approach for islet replacement. Cancers and pathogens have been noted to upregulate sialyltransferases and engage inhibitory Siglec receptors to dampen immune rejection. Previous studies in the lab found that islet resident macrophages express the inhibitory Siglec-E receptor, which binds sialic acid residues generated by the sialyltransferase ST8Sia6. This leads to the central hypothesis that induced ST8Sia6 expression in the beta cells of the islet can protect against autoimmune rejection. To test this, we have developed a novel mouse on the non-obese diabetic background that expresses ST8Sia6 in a beta cell specific manner, and have shown robust protection from disease. The central hypothesis will be addressed in two specific aims. The mechanistic basis of protection from spontaneous and induced autoimmunity will be explored. Immune profiling via flow cytometry will help elucidate the cellular and molecular events protecting from autoimmune activity. This project recognizes the complex dynamics of the immune response and considers both innate and adaptive mediators of autoimmunity in investigating a novel immunomodulatory path. Additionally, the potential therapeutic applications of this work will be tested. Our genetic model includes a tetracycline-off parameter, allowing for temporal studies investigating the minimum required time of ST8Sia6 expression for robust protection or the ability of ST8Sia6 to alter the autoimmune disease process once initiated. We will also employ novel islet transplantation models to determine whether ST8Sia6 expressing beta cells can restore glycemic control without immunosuppression. Ultimately, this work will contribute to improved understanding of autoimmunity and a potentially tissue-intrinsic approach to avoid immune rejection.