Transforming Growth Factor beta in T-Cell Homeostasis and Tolerance

T 细胞稳态和耐受性中的转化生长因子 β

• 批准号: 7023314
• 负责人: THOMAS DOETSCHMAN
• 金额: $ 38.37万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023314
• 关键词: homeostasis; transforming growth factors

DESCRIPTION (provided by applicant): Project Summary: T-cell homeostasis is an essential process for maintaining peripheral lymphocyte pool size. T cells must provide a diverse repertoire of antigen recognition to effectively recognize and destroy pathogens that they encounter. Antigen-specific T-cell pools are expanded during viral infection and are contracted after the initial viral clearance to make space for the entire T-cell repertoire. This is a tightly regulated process since the space available for lymphocytes is limited. Transforming Growth Factor ? signaling is required to prevent autoimmune disease and dysregulation of T-cell homeostasis. Normally, T cells must interact with self-MHC molecules for their survival, maintenance and homeostatic expansion, but under some pathological conditions such interactions cause inappropriate activation of T cells leading to autoimmune disease. Characterization of TGF??-deficient mice has revealed that their autoimmune disease results from spontaneous activation of their T cells in response to self-antigen recognition by having an inappropriately low threshold level of activation through a Calcium-Calcineurin signaling cascade. Elimination of T cells or their self-antigen recognition is sufficient to prevent autoimmune disease in these mice, and reducing calcineurin signaling drastically attenuates their autoimmune disease. In addition, it is known that without TGF? signaling there are less T-regulatory cells, the cells that mediate immune tolerance. Here we propose to investigate mechanisms and processes underlying the role of TGF? in the regulation of T-cell homeostasis and self-tolerance. Firstly, we will address how TGF?1 regulates T-cell pool size using an Ovalbumin-specific T-cell receptor transgenic TGF?1-deficient mouse strain. Adoptive transfer and Ovalbumin activation studies will be used. Secondly, we will study the role of TGF?? and its signaling pathways in peripheral T-cell regulation. T-regulatory cell transfer to effect tolerizing activity will be performed and the passive or infectious nature of that activity will be determined. Relevance: Dysregulation of homeostatic process has been implicated in many human diseases such as AIDS, leukemia, inflammatory bowl disease, and autoimmune diseases such as type 1 diabetes, multiple sclerosis and arthritis. Processes involved in T-cell homeostasis such as lymphocyte activation, survival and death are presently under intensive study because of their relevance to these diseases. The information gained from these studies will be useful for developing therapies for the induction of tolerance during transplantation, for enhancing tumor vaccine potential, and for the prevention of autoimmune disease.

描述（由申请人提供）： 项目摘要：T 细胞稳态是维持外周淋巴细胞池大小的重要过程。 T 细胞必须提供多种抗原识别能力，才能有效识别并消灭它们遇到的病原体。抗原特异性 T 细胞库在病毒感染过程中会扩大，并在最初的病毒清除后收缩，为整个 T 细胞库腾出空间。这是一个受到严格监管的过程，因为淋巴细胞可用的空间有限。转化生长因子？信号传导是预防自身免疫性疾病和 T 细胞稳态失调所必需的。正常情况下，T 细胞必须与自身 MHC 分子相互作用才能生存、维持和稳态扩张，但在某些病理条件下，这种相互作用会导致 T 细胞不适当的激活，从而导致自身免疫性疾病。 TGFα缺陷小鼠的特征表明，它们的自身免疫性疾病是由于T细胞响应自身抗原识别而自发激活，通过钙-钙调神经磷酸酶信号级联反应具有不适当的低激活阈值水平。消除 T 细胞或其自身抗原识别足以预防这些小鼠的自身免疫性疾病，而减少钙调神经磷酸酶信号传导可大大减轻其自身免疫性疾病。另外，众所周知，没有TGF？信号传导 T 调节细胞（介导免疫耐受的细胞）较少。在这里，我们建议研究 TGF 作用的机制和过程？ T 细胞稳态和自我耐受的调节。首先，我们将讨论 TGF?1 如何使用卵清蛋白特异性 T 细胞受体转基因 TGF?1 缺陷小鼠品系调节 T 细胞池大小。将使用过继转移和卵清蛋白激活研究。其次，我们来研究一下TGF的作用？？及其在外周 T 细胞调节中的信号通路。将进行T调节细胞转移以实现耐受活性，并确定该活性的被动或感染性质。相关性：体内平衡过程失调与许多人类疾病有关，例如艾滋病、白血病、炎性肠病，以及 1 型糖尿病、多发性硬化症和关节炎等自身免疫性疾病。涉及 T 细胞稳态的过程，例如淋巴细胞激活、存活和死亡，由于它们与这些疾病的相关性，目前正在深入研究。从这些研究中获得的信息将有助于开发在移植过程中诱导耐受的疗法、增强肿瘤疫苗的潜力以及预防自身免疫性疾病。