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

TGF-β 对粘膜和全身 T 细胞免疫和耐受的调节

基本信息

批准号：
7733895
负责人：
Wanjun Chen
金额：
$ 104.87万
依托单位：
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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.

我们的研究兴趣是阐明TGF-β调节粘膜和全身T细胞免疫和耐受的机制，以便提供在动物模型中操纵T细胞免疫与耐受的靶点，从而开发针对相关人类疾病（如自身免疫、癌症和传染病）的潜在疗法。具体来说，我们想了解 (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后的免疫耐受，以及 (3) 如何调节粘膜 T 细胞中的 TGF-β 信号转导和 TGF-β 产生。最近，我们重点关注正常小鼠和基因工程小鼠中 CD4+CD25+ T 调节细胞的分离和表征，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T调节细胞发育的主基因Foxp3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。这一发现不仅对了解 CD4+CD25+ 调节性 T 细胞的生成产生重大影响，而且首次有可能设计策略，根据需要修饰外周有限和/或数量不足的 T 调节细胞，以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 Foxp3 表达的分子途径，以定义 CD4+CD25+ T 细胞如何在粘膜淋巴系统内外发育，并开始解开 TGF-β 在 T 调节细胞介导的免疫耐受中的作用之谜。我们还打算运用从基础研究中获得的知识来操纵动物模型中的 T 细胞免疫与耐受性，从而开发针对相关人类疾病的潜在疗法，特别关注 NIDCR 任务相关疾病，例如干燥综合征和口腔癌、头颈癌。