TGF-beta Regulation of Mucosal and Systemic T Cell Immunity and Tolerance

我们的研究兴趣是阐明tgf - β调节粘膜和全身T细胞免疫和耐受性的机制，为在动物模型中操纵T细胞免疫和耐受性提供靶点，以开发潜在的治疗相关人类疾病，如自身免疫、癌症和传染病。具体而言，我们希望了解(1)tgf - β如何参与粘膜和其他淋巴组织中CD4+CD25+ T调节细胞（Treg）的功能和发育，(2)tgf - β如何调节T程序性细胞死亡和随之而来的免疫耐受，(3)如何调节粘膜T细胞中tgf - β的信号转导和tgf - β的产生，以及(4)tgf - β调节口腔粘膜上皮内淋巴细胞（iel）的细胞和分子机制。最近，我们专注于从正常和基因工程小鼠中分离和表征CD4+CD25+ T调节细胞，并剖析了tgf - β在T调节细胞介导的免疫抑制中的作用。重要的是，我们还发现tgf - β是通过诱导Foxp3 （T调节细胞发育的主基因）将初始CD4+CD25-外周T细胞转化为CD4+CD25+ T调节细胞的关键因素。这一发现不仅对理解CD4+CD25+调节性T细胞的产生有重大影响，而且还首次使设计策略成为可能，根据需要修饰外周有限和/或不足数量的T调节性细胞，用于自身免疫性疾病和炎症的治疗干预。此外，通过t细胞特异性条件tgf - β受体1敲除小鼠，我们已经证明tgf - β信号对于胸腺中天然Foxp3+ Tregs的发育和产生也至关重要。在相关研究中，我们已经证明巨噬细胞和未成熟树突状细胞清除凋亡的T细胞与给予自身抗原肽相结合，导致抗原特异性Tregs的产生，从而抑制自身免疫并诱导长期免疫耐受。此外，我们还在小鼠模型中发现d -甘露糖诱导Treg细胞并抑制I型糖尿病和肺部炎症。我们的下一步工作是破译tgf - β诱导Foxp3表达的分子途径，以确定CD4+CD25+ T细胞是如何在粘膜淋巴系统内外发育的，并开始解决tgf - β在T调节细胞介导的免疫耐受中的作用之谜。我们还打算将我们在动物模型基础研究中获得的知识应用于开发相关人类疾病的潜在治疗方法，包括炎症/自身免疫性疾病、癌症和传染病，特别关注NIDCR任务相关疾病，如伤口愈合、口腔相关炎症和口腔癌。

Our research interest is to elucidate mechanisms of TGF-beta regulation of mucosal and systemic T cell immunity and tolerance, in order to offer targets to manipulate T cell immunity versus tolerance in animal models to develop potential therapies for relevant human diseases such as autoimmunity, cancer and infectious diseases. Specifically we would like to understand (1) how TGF-beta is involved in the function and development of CD4+CD25+ T regulatory cells (Treg) in mucosal and other lymphoid tissues, (2) how TGF-beta regulates T programmed cell death and the consequent immune tolerance, (3) how TGF-beta signal transduction and TGF-beta production in mucosal T cells are regulated, and (4) The cellular and molecular mechanisms of TGF-beta regulation of oral mucosal intraepithelial lymphocytes (IELs). Recently, we have focused on the isolation and characterization of CD4+CD25+ T regulatory cells from normal and genetically engineered mice and dissected the involvement of TGF-beta in immunosuppression mediated by T regulatory cells. Importantly, we have also identified that TGF-beta is a critical factor in the conversion of naive CD4+CD25- peripheral T cells to CD4+CD25+ T regulatory cells through induction of Foxp3, a master gene for T regulatory cell development. This finding not only has significant impact on understanding the generation of CD4+CD25+ regulatory T cells, but also makes it possible for the first time to design strategies to embellish the limited and/or inadequate numbers of T regulatory cells in the periphery, as needed, for therapeutic intervention in autoimmune diseases and inflammation. In addition, with the T-cell specific conditional TGF-beta receptor I knockout mice, we have shown that TGF-beta signaling is also critical for the development and generation of natural Foxp3+ Tregs in the thymus. In related studies, we have demonstrated that combination of clearance of apoptotic T cells by macrophages and immature dendritic cells with administration of autoantigenic peptide leads to generation of antigen-specific Tregs that in turn suppress autoimmunity and induce long-term immune tolerance. Furthermore, we have also discovered that D-mannose induces Treg cells and suppresses type I diabtes and lung inflammation in mouse models. Our immediate next steps are to decipher the molecular pathway(s) by which TGF-beta induces Foxp3 expression to define how CD4+CD25+ T cells are developed in and out of mucosal lymphoid systems, as well as to begin to resolve the mystery of TGF-beta's role in T regulatory cell mediated immune tolerance. We also intend to apply the knowledge obtained from our basic research in animal models to develop potential therapy for relevant human diseases including inflammation/autoimmune diseases, cancer and infectious diseases, with special attention to NIDCR mission relevant diseases such as wound healing, oral cavity associated inflammation and oral cancer.