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

基本信息

批准号：
7759458
负责人：
THOMAS DOETSCHMAN
金额：
$ 36.55万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-15 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7759458
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 Research Personnel Role Self Tolerance Signal Pathway Signal Transduction T cell regulation T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Transforming Growth Factor beta Transforming Growth Factors Transgenic Mice Transgenic Organisms Transplantation Upper arm Viral Virus Diseases autocrine cell type cytokine human disease in vivo leukemia paracrine pathogen prevent programs receptor response therapy development thymocyte

项目摘要

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.

项目摘要：T 细胞稳态是维持外周淋巴细胞池的重要过程尺寸。 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大，并且在最初的病毒清除后收缩，为整个 T 细胞库腾出空间。这是一个严密的由于淋巴细胞可用的空间有限，因此该过程受到调节。转化生长因子 (3 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。通常，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，但是在某些病理条件下，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。 TGF01 缺陷小鼠的特征表明，它们的自身免疫性疾病这是由于 T 细胞响应自身抗原识别而自发激活的结果通过钙-钙调神经磷酸酶信号级联的激活阈值水平不适当地低。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，并且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。此外，据了解，如果没有 TGF(3 信号传导)，调节 T 细胞（介导免疫耐受的细胞）就会减少。在这里，我们提议研究 TGFp 在 T 细胞调节中的作用机制和过程体内平衡和自我耐受。首先，我们将讨论 TGF01 如何使用卵清蛋白特异性T细胞受体转基因TGF(31缺陷小鼠品系。过继转移和将使用卵清蛋白激活研究。其次，我们将研究TGF(31)的作用及其信号传导外周 T 细胞调节途径。将进行 T 调节细胞转移以实现耐受活性该活动的被动性或传染性将被确定。相关性：体内平衡过程的失调与许多人类疾病有关，例如艾滋病、白血病、炎症性肠病和自身免疫性疾病，如 1 型糖尿病、多发性硬化症硬化和关节炎。参与 T 细胞稳态的过程，例如淋巴细胞激活、存活和由于死亡与这些疾病的相关性，目前正在深入研究。信息从这些研究中获得的成果将有助于开发诱导耐受性的疗法移植，用于增强肿瘤疫苗的潜力，以及预防自身免疫性疾病。