iSTAR Tregs

ABSTRACT Regulatory T cells (Tregs) are a small subset of T cells that are vital to immune self-tolerance. They function by dominantly controlling the activities of other immune cells. In mouse models of type 1 diabetes (T1D), a single infusion of islet-specific Tregs prevents and stably reverses autoimmune diabetes. In these mouse models, infused Tregs accumulate in pancreatic islets and arrest autoimmune aggression against islet beta cells by expressing immune suppressive functions locally. Early-phase clinical trials of Treg cell therapy in patients with T1D have shown that it is feasible to produce billions of patients’ own Tregs for infusion and the therapy is well tolerated and safe. These pioneering efforts have paved the way for the development of next-generation Treg therapy aiming at establishing efficacy. The research program described in this proposal focuses on a critical need for a strategy to increase effectiveness by targeting human Tregs to the pancreatic islets and to monitor the targeting efficacy in patients. The proposed strategy is guided by the overarching hypothesis that shared, dominant immunopeptides on the surface of beta cells are highly specific anchors for islet targeting. Tregs can be engineered to target these anchors to deliver their immune regulatory function locally in the islets. Moreover, successful engagement of Tregs with beta cells can be monitored using an engineered biomarker released into the peripheral blood. Aim 1 will define the immunopeptidome of pancreatic beta cells. Aim 2 will develop a cellular engineering strategy to target Tregs efficiently and safely to pancreatic islets. Aim 3 will develop a barcode biomarker that is released by activated Tregs into the peripheral blood. These projects together aim to develop islet- specific TCR activation relay (iSTAR) Tregs. We have built a team of three investigators with complementary expertise in immunology, beta cell biology, and technology development. The proposed program synergizes our expertise to tackle the challenges in precision targeting of pancreatic islets for the preservation of beta cell mass in T1D.