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

我们的研究兴趣是阐明TGF-β调节粘膜和系统性T细胞免疫和耐受的机制，以提供在动物模型中操纵T细胞免疫与耐受的靶点，从而开发用于相关人类疾病如自身免疫、癌症和感染性疾病的潜在疗法。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CD 4 + CD 25 + T调节细胞（Treg）的功能和发育，（2）TGF-β如何调节T细胞程序性死亡和随后的免疫耐受，以及（3）TGF-β信号转导和粘膜T细胞中TGF-β的产生如何受到调节。 最近，我们集中于从正常和基因工程小鼠中分离和鉴定CD 4 + CD 25 + T调节细胞，并剖析了TGF-β参与T调节细胞介导的免疫抑制。重要的是，我们还确定了TGF-β是通过诱导Foxp 3（T调节细胞发育的主基因）将初始CD 4 + CD 25-外周T细胞转化为CD 4 + CD 25 + T调节细胞的关键因子。这一发现不仅对理解CD 4 + CD 25+调节性T细胞的产生具有重大影响，而且还首次使设计策略以根据需要修饰外周中有限和/或不足数量的T调节性细胞成为可能，用于自身免疫性疾病和炎症的治疗干预。 我们接下来的步骤是破译TGF-β诱导Foxp 3表达的分子途径，以确定CD 4 + CD 25 + T细胞是如何在粘膜淋巴系统内外发育的，以及开始解决TGF-β在T调节细胞介导的免疫耐受中的作用之谜。我们还打算应用从我们的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，以开发相关人类疾病的潜在疗法，特别关注NIDCR使命相关疾病，如干燥综合征和口腔癌和头颈癌。

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. 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-betas 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.