The objective of this grant is identifying small molecules to control activity of regulatory T cells (Treg) using reporter systems for mouse and human foxp3 gene expression. Treg are originally identified as suppressor T cells and essential in preventing autoimmune disease. Therefore, enhancing Treg activity may offer new therapeutic strategies in re-programing immunity towards tolerance in autoimmune diseases and transplantations. Although Treg prevent autoimmune disease, there is an unexpected contribution by Treg in enhancing risk of microbial (including viral and bacterial) infection and increasing cancer cell survivability. Cytotoxic CD8+ T cells response leads to clearance of microbial pathogens and cancer cells, but these activities seem to be suppressed by Treg. Recent studies show that there is an increased frequency of Treg in microbial infected and cancer patients, within infected tissues, tumors, and in circulation. Therefore, inhibiting Treg activity may offer new therapeutic strategies for infectious diseases and cancer as well. Development and function of Treg are regulated by a transcription factor FOXP3, indicating that we can manipulate Treg activity through controlling FOXP3 gene expression for therapies of autoimmune and infectious diseases and cancer. To this end, we and many other groups have been studying regulation of Foxp3 expression. Foxp3 gene expression is controlled through at least four regulatory regions located in the promoter and conserved non- cording sequences (CNS1, CNS2 and CNS3). We demonstrated that cRel (in promoter), NFAT and Smad3 (in CNS1) and STAT5 and AP1 (in CNS2) regulate Foxp3 gene expression, and that inhibitors for activation of these transcription factors can block development and activity of Treg. However, these important transcription factors do not only regulate Foxp3 gene expression but also anti-microbial and anti-tumor immune responses, suggesting that these inhibitors are not suitable for therapies of infectious disease and cancer. Since Foxp3 gene expression is regulated by extremely complicated mechanisms through at least four regulatory regions, seeking small molecules to control Foxp3 gene expression is also difficult. To resolve these problems, we generated reporter systems for mouse and human foxp3 gene expression. Ability of these systems are validated by using inhibitors of transcription factors involved in Foxp3 gene expression, and we also found that a mTOR inhibitor Torin1 could enhance FOXP3 gene expression using this system. We will, therefore, identify more potential small molecules using these reporter systems to develop therapeutic strategies for autoimmune and infectious diseases, and cancer.
Regulatory T cells (Treg) play an important role in preventing autoimmune disease. However, there is an unexpected contribution by Treg in enhancing risk of infection and tumor cell survivability. Therefore, manipulation of Treg holds promise as a therapeutic option for autoimmune and infectious diseases, and cancer. Since development and function of Treg is regulated by a transcription factor FOXP3, we will seek small molecules to control FOXP3 gene expression and consequently Treg activity.
