Type 1 diabetes (T1D) is one of the most prevalent chronic childhood diseases worldwide. In addition to its negative impact on quality of life for patients and their families, the disease also poses a significant financial burden on society. Thus, a curative solution, instead of the current maintenance therapy, is urgently needed. One such curative treatment shown to be very successful in mouse models is the infusion of autologous regulatory T cells (Tregs). Tregs are a small subset of CD4+ T lymphocytes that are primarily responsible for controlling pathogenic autoimmune responses in the periphery. Mounting evidence in animal models and patients demonstrates that T1D is associated with an imbalance between pathogenic T cells and Tregs. Treg therapy restores the balance and enables the immune system to regain self-control. With these encouraging results, a clinical trial of Treg-based therapy is being actively developed and is scheduled to start in 2009. At this juncture, it is important to understand the cellular and molecular basis of Treg function in controlling T1D. Our previous experiments demonstrate that a single infusion of islet-antigen-specific Tregs isolated from BDC2.5 T cell receptor transgenic mice (BDC Tregs) can prevent and reverse diabetes in the NOD mice. The BDC Tregs migrate to pancreatic lymph nodes and islets. In the pancreatic LN, they engage dendritic cells and effectively block further activation of pathogenic T cells by dendritic cells. How BDC Tregs halt 2 cell destruction in the inflamed islets has not been studied. In this grant application, we propose to systematically investigate the mechanism of T1D control in the NOD mice by BDC Tregs. We will determine the direct cellular target of BDC Tregs in vivo, and identify their impact on the ongoing inflammatory response in the islets at cellular and molecular levels. We will further determine the molecular profile of the therapeutic Tregs and identify molecule(s) responsible for their protective effect in vivo. Through the studies proposed in this grant application, we expect to gain better understanding of the pathogenic events critical for T1D progression and how therapeutic Tregs control these processes. The insight gained from these mechanistic studies will help to improve the design of Treg- based cellular therapy and to identify new targets for therapeutic intervention of T1D.

Public Health Relevance

Type 1 diabetes is a chronic childhood disease that results from an immune-mediated destruction of the insulin-producing 2 cells. Regulatory T cells constitute a small population of immune cells that is mainly responsible for preventing unwanted immune response in healthy people. In animal models, regulatory T cell therapy can effectively prevent and reverse type 1 diabetes. Studies proposed herein are designed to understand the cellular and molecular basis for regulatory T cell control the disease. The insight gained from these mechanistic studies will help to improve the design of regulatory T cell-based therapy for patients and to identify new targets for therapeutic intervention of type 1 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Klementowicz, Joanna E; Mahne, Ashley E; Spence, Allyson et al. (2017) Cutting Edge: Origins, Recruitment, and Regulation of CD11c+ Cells in Inflamed Islets of Autoimmune Diabetes Mice. J Immunol 199:27-32
Lindsay, Robin S; Corbin, Kaitlin; Mahne, Ashley et al. (2015) Antigen recognition in the islets changes with progression of autoimmune islet infiltration. J Immunol 194:522-30
Mahne, Ashley E; Klementowicz, Joanna E; Chou, Annie et al. (2015) Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes. J Immunol 194:3147-55
Spence, Allyson; Klementowicz, Joanna E; Bluestone, Jeffrey A et al. (2015) Targeting Treg signaling for the treatment of autoimmune diseases. Curr Opin Immunol 37:11-20