Autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes and lupus, etc., affect approximately 50 million Americans. The immune responses of self-reactive T lymphocytes play critical roles in autoimmune diseases. Therefore, identification of novel molecules that regulate T cell immune functions are important for a better understanding of the mechanisms underlying the disease development and for seeking novel therapies. During the current finding period, we have discovered that the type III histone deacetylase Sirt1 as a critical suppressor to T cell immunity and macrophage activation by suppressing the transcription factors AP-1, indicating Sirt1 as a potential therapeutic target for autoimmune and inflammatory diseases. In fact, we further demonstrated that the Sirt1 activator resveratrol prevents/treats type 1 diabetes in mice. Our preliminary study of the currentcompetitive renewal application demonstrates that the deacetylase Sirt1 and the acetyltransferase GCN5 oppositely regulate T cell activation. Genetic deletion of GCN5 gene inhibits T cell immune responses in mice, identifying GCN5 as a critical positive regulator for T cell immunity. Interestingly, treatment of mice with GCN5 specific inhibitor attenuated autoimmune disease development. Therefore, based on the above preliminary findings, we propose that the histone deacetylase Sirt1 is a negative regulator and the acetyltransferase GCN5 is a positive regulator for T cell immunity, and that the Sirt1 activator and GCN5 inhibitor have great therapeutic potentials in treatment of autoimmune diseases. This project is to address this hypothesis using the state-of-art approaches of both immunological and molecular studies. Results from this proposed study discover novel molecular mechanisms behind Sirt1 and GCN5 in T cell activation and autoimmunity, providing rationales for the uses of Sirt1 deacetylase activators and GCN5 acetyltransferase inhibitors in treating/preventing autoimmune diseases.

Public Health Relevance

This study identifies the histone deacetylase Sirt1 as a negative regulator and the acetyltransferase GCN5 as a positive regulator for T cell immune response. Therefore, Sirt1 activators and GCN5 inhibitors have great therapeutic potentials in the treatment of autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Peyman, John A
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Northwestern University at Chicago
Schools of Medicine
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