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

我们的研究兴趣是阐明转化生长因子-β对粘膜和全身T细胞免疫和耐受的调节机制，为在动物模型中调控T细胞免疫和耐受提供靶点，以开发潜在的治疗相关人类疾病的方法，如自身免疫、癌症和传染病。具体地说，我们想了解(1)转化生长因子-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)转化生长因子-β如何调节T细胞程序性死亡和由此产生的免疫耐受；(3)转化生长因子-β信号转导和转化生长因子-β在粘膜T细胞中的产生是如何调节的。最近，我们从正常小鼠和基因工程小鼠中分离和鉴定了CD4+CD25+T调节细胞，并剖析了转化生长因子-β参与T调节细胞介导的免疫抑制。重要的是，我们还发现转化生长因子-β是通过诱导T细胞发育的主要基因Foxp3，将原始的CD4+CD25-外周T细胞转化为CD4+CD25+T细胞的关键因子。这一发现不仅对理解CD4+CD25+调节性T细胞的产生具有重大影响，而且还使首次有可能设计策略，根据需要美化外周数量有限和/或不足的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，在T细胞特异性条件性转化生长因子-β受体I基因敲除小鼠中，我们已经证明转化生长因子-β信号对胸腺中自然Foxp3+Tregs的发育和生成也是至关重要的。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细胞会触发转化生长因子-β1的分泌，而转化生长因子-β在CD3特异性抗体介导的免疫耐受中起关键作用。我们下一步的工作是破译转化生长因子-β诱导FOXP3表达的分子途径(S)，以确定粘膜淋巴系统中CD_4+CD_(25+)+T细胞是如何发育的，并开始解开转化生长因子-β在T调节细胞介导的免疫耐受中的作用之谜。我们还打算应用从基础研究中获得的知识，在动物模型中操纵T细胞免疫与耐受性，以开发针对相关人类疾病的潜在疗法，并特别关注与NIDCR任务相关的疾病，如干燥综合征和口腔癌、头颈癌。

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, and (3) how TGF-beta signal transduction and TGF-beta production in mucosal T cells are regulated. 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 clearance of apoptotic T cells by macrophages and immature dendritic cells triggers TGF-beta; secretion, which plays a critical role in CD3-specific antibody mediated immune tolerance. 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 to manipulate T cell immunity versus tolerance in animal models to develop potential therapy for relevant human diseases, with special attention to NIDCR mission relevant diseases, such as Sjogrens syndrome and oral and head and neck cancers.