Engineered Regulatory T cells with Enhanced Stability and Suppression for Autoimmunity

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PROJECT SUMMARY Autoimmune diseases are characterized by the immune system attacking the body, adversely affecting over 23 million Americans a year. Current standards of care often only alleviate symptoms, leave patients dependent on therapies, and increase their susceptibility to infection, necessitating new treatment paradigms. The recent development of engineered cell-based therapies has allowed us to harness a suppressive T cell phenotype known as regulatory T cells (Tregs) and design them to target sites of autoimmunity. However, instability of the Treg phenotype and inability to drive immunosuppressive functions have hindered their therapeutic potential and widespread adoption in the clinic. We seek to harness novel technologies from genome and receptor engineering to build a platform for engineering of highly stable and suppressive Tregs that become the basis for future cell- based therapies against autoimmunity. This platform is enabled by two novel cell engineering techniques that I recently developed, including a highly efficient and specific knock-in strategy that stabilizes transgene expression and a receptor platform that activates customized cytokine pathways. Specifically, we aim to 1) generate a highly stable Treg phenotype by leveraging the knock-in strategy to express the Treg driving transcription factor, FOXP3, in CD4+ T cells, 2) identify and characterize suppression enhancement pathways by high-throughput cell-based screens utilizing my receptor platform, and 3) assess the therapeutic benefit of these novel engineered Tregs in a mouse model of Graft-vs-Host Disease. This work results in a novel discovery and engineering platform that creates Tregs that can be adapted for targeted cell-based therapies against a plethora of autoimmune diseases. The completion of the proposed work creates new data, new pathways, and new technologies to improve the survival and the function of Treg therapies, improving their translation potential and bringing them closer to helping the people who need it most.