Determining Regulatory Pathways That Maintain FOXP3 in Human T regulatory Cells

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Autoimmune diseases such as rheumatoid arthritis (RA) and Type I diabetes are driven by over-activated immune cells. A type of immune cell called regulatory T cell (Tregs) can efficiently stop uncontrolled immune system activation and prevent autoimmune diseases. Pilot clinical trials using Tregs as a therapy for diseases such as colitis, type 1 diabetes and other immune related diseases have shown promising results. Furthermore, evidence of Treg cell function is apparent in patients with mutation in Treg specific gene called FoxP3. Foxp3 mutation results in severe autoimmune disease in humans which is known as IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome. Therefor all these observations in humans clearly demonstrate that Tregs are indispensable for controlling over-activation of the immune system.However, how Foxp3 expression in Tregs are controlled within the human body is still not fully understood. Therefore, the goal of this grant proposal is to understand how human Foxp3 is regulated.We have discovered a new regulatory molecule (asparaginyl endopeptidase; AEP) that can control Treg cell function in mice. AEP directly cleaved and degraded FoxP3 protein in Tregs and abolished their suppressive function. In addition to this observation, we also found that AEP expression in Tregs can be significantly down-regulated by a receptor on Tregs called programmed cell death receptor-1 (PD-1). By extending our mouse studies in humans, we have discovered the expression of AEP in human Tregs but its function and importance in human Treg cells is unknown. In this grant proposal, we aim to understand the function and importance of AEP in human Tregs and other T helper cell subsets. We will study whether:1. AEP controls FoxP3 in human Treg cells and whether blocking AEP increases Treg cell function2. If PD-1 and other similar coreceptors can block AEP expression in Tregs3. Determine if AEP is expressed in other T helper cell subsets in humans and test its function within these subsets.We propose that if AEP has a similar function in human Tregs, then it would be possible to target AEP in order to generate engineered Treg cell therapies that can efficiently control a variety of autoimmune disease. Such targeted therapies will enable a better quality of life for those patients who suffer from chronic autoimmune diseases. The current standard of care for these patients include global immune suppressive drugs such as corticosteroids; the long-term use of which can result in unwanted side effects. Engineered cell therapies can not only control autoimmunity but can be deleted from the body on reaching immune cell control. Success of these therapies is already apparent in the cancer field therefore providing a proof of principle for generating similar cell therapies for treating autoimmuntiy