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: 7775091
• 负责人: THOMAS DOETSCHMAN
• 金额: $ 37.27万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7775091
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Affect; Antigens; Apoptosis; Arthritis; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmune Process; Calcineurin; Calcium; Cancer Vaccines; Cell Culture Techniques; Cell physiology; Cells; Cessation of life; Contracts; Dependency; Development; Disease; Dominant-Negative Mutation; Effector Cell; Exhibits; Generations; Hand; Homeostasis; Immune Tolerance; Immune system; In Vitro; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Knock-out; Ligands; Lymphocyte; Lymphocyte Activation; MADH3 gene; Maintenance; Mature T-Lymphocyte; Mediating; Molecular; Multiple Sclerosis; Mus; Nature; Newborn Infant; Ovalbumin; Ovum; Pathway interactions; Peptides; Peripheral; Play; Population; Prevention; Process; Production; Regulation; Regulatory T-Lymphocyte; Research Personnel; Role; Self Tolerance; Signal Pathway; Signal Transduction; T cell regulation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Transplantation; Viral; Virus Diseases; arm; autocrine; cell type; cytokine; human disease; in vivo; leukemia; paracrine; pathogen; prevent; programs; receptor; response; therapy development; thymocyte

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 (3 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 TGF01-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(3 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 TGFp in the regulation of T-cell homeostasis and self-tolerance. Firstly, we will address how TGF01 regulates T-cell pool size using an Ovalbumin-specific T-cell receptor transgenic TGF(31-deficientmouse strain. Adoptive transfer and Ovalbumin activation studies will be used. Secondly, we will study the role of TGF(31 and its signaling pathways in peripheral T-cell regulation. T-regulatory cell transfer to effect tolerizing activity will beperformed 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.

项目概述：T细胞稳态是维持外周血淋巴细胞库的重要过程 尺寸T细胞必须提供多样化的抗原识别库才能有效识别和破坏 他们遇到的病原体。抗原特异性T细胞库在病毒感染期间扩增， 在最初的病毒清除后收缩，为整个T细胞库腾出空间。这是一个紧密的 由于淋巴细胞可用的空间有限，因此这是一个受调节的过程。转化生长因子（3 需要信号传导来预防自身免疫疾病和T细胞稳态失调。一般来说，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， 在某些病理条件下，这种相互作用引起T细胞的不适当活化， 自身免疫性疾病TGF 01缺陷小鼠的特征表明，它们的自身免疫性疾病 结果从自发激活的T细胞响应自身抗原识别，通过具有 通过钙-钙神经磷酸酶信号级联不适当地降低激活阈值水平。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， 减少钙调磷酸酶信号传导显著减弱了他们的自身免疫性疾病。此外，据了解， 没有TGF β 1信号传导，调节免疫耐受性的T调节细胞较少。这里我们 建议研究TGF β在调节T细胞增殖中的作用的机制和过程， 自我平衡和自我耐受。首先，我们将使用一种新的方法来解决TGF 01如何调节T细胞池的大小。 卵清蛋白特异性T细胞受体转基因TGF β 1缺陷小鼠过继转移和 将使用卵清蛋白活化研究。其次，我们将研究TGF β 1及其信号通路在肿瘤细胞中的作用 外周T细胞调节途径。将进行调节性T细胞转移以实现耐受活性 并将确定该活动的被动或传染性质。 相关性：体内平衡过程的失调与许多人类疾病有关， 艾滋病、白血病、炎性肠病和自身免疫性疾病如1型糖尿病、多发性 硬化症和关节炎。参与T细胞稳态的过程，如淋巴细胞活化、存活和 由于死亡与这些疾病的关系，目前正在进行深入研究。的信息 从这些研究中获得的信息将有助于开发用于诱导耐受的治疗方法， 移植，用于增强肿瘤疫苗潜力，和用于预防自身免疫性疾病。