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

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, (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 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. We have also discovered that TGF-beta controls the development of mucosal IELs in the gut. 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.
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。具体来说,我们想了解(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细胞中的TGF-β信号转导和TGF-β产生,口腔黏膜上皮内淋巴细胞(IELs)TGF-β调节的细胞和分子机制。 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。 此外,通过T细胞特异性条件性TGF-β受体I敲除小鼠,我们已经表明TGF-β信号传导对于胸腺中天然Foxp 3 + TcB的发育和产生也是至关重要的。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对凋亡T细胞的清除触发TGF-β分泌,其在CD 3特异性抗体介导的免疫耐受中起关键作用。我们还发现TGF-β控制肠道中粘膜IEL的发展。我们的下一步是破译TGF-β诱导Foxp 3表达的分子途径,以确定CD 4 + CD 25 + T细胞如何在粘膜淋巴系统内外发育,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。

项目成果

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Wanjun Chen其他文献

Wanjun Chen的其他文献

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{{ truncateString('Wanjun Chen', 18)}}的其他基金

Immunotherapy of inflammation, autoimmune disease and cancer
炎症、自身免疫性疾病和癌症的免疫治疗
  • 批准号:
    10920187
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
TGF-beta Regulation of Mucosal and Systemic T Cell Immun
TGF-β 对粘膜和全身 T 细胞免疫的调节
  • 批准号:
    6966385
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
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
  • 批准号:
    7967013
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
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
  • 批准号:
    7733895
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
Immunotherapy of inflammation, autoimmune disease and cancer
炎症、自身免疫性疾病和癌症的免疫治疗
  • 批准号:
    10487166
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
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
  • 批准号:
    8553316
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
TGF-beta Regulation of Mucosal and Systemic T Cell Immun
TGF-β 对粘膜和全身 T 细胞免疫的调节
  • 批准号:
    7318843
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
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
  • 批准号:
    10920182
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
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
  • 批准号:
    7593351
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:
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
  • 批准号:
    10261201
  • 财政年份:
  • 资助金额:
    $ 204万
  • 项目类别:

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