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: 7197991
• 负责人: THOMAS DOETSCHMAN
• 金额: $ 36.4万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197991
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Affect; Antigens; Apoptosis; Arthritis; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmune Process; Calcineurin; Calcium; Cancer Vaccines; Cell physiology; Cells; Cessation of life; Condition; Contracts; Cultured Cells; 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; Mouse Strains; Multiple Sclerosis; Mus; Nature; Neoadjuvant Therapy; 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; size; thymocyte

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细胞稳态是维持周围淋巴细胞池尺寸的重要过程。 T细胞必须提供多种抗原识别的曲目，以有效地识别并破坏它们遇到的病原体。抗原特异性的T细胞池在病毒感染期间扩展，并在初始病毒清除率后收缩，以为整个T细胞曲目提供空间。这是一个严格调节的过程，因为可用于淋巴细胞的空间有限。改变生长因子？需要信号传导以防止自身免疫性疾病和T细胞稳态失调。通常，T细胞必须与自我MHC分子相互作用以生存，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细胞的不适当激活导致自身免疫性疾病。 TGF ??-缺乏小鼠的表征表明，它们的自身免疫性疾病是由于其T细胞自发激活而响应自抗原识别而导致的，这是通过通过钙 - 钙调蛋白信号级联钙质的不适当较低的阈值激活水平而引起的。消除T细胞或其自我抗原识别足以预防这些小鼠的自身免疫性疾病，并且降低钙调神经蛋白信号会大大减轻其自身免疫性疾病。另外，众所周知，没有TGF？信号传达的T调节细胞是介导免疫耐受性的细胞。在这里，我们建议研究TGF作用的基础机制和过程？在调节T细胞体内平衡和自我耐受的过程中。首先，我们将使用椭圆形特异性T细胞受体转基因TGF？1缺陷小鼠应变来调查TGF？1如何调节T细胞池尺寸。将使用收养转移和椭圆形激活研究。其次，我们将研究TGF的作用？及其在周围T细胞调节中的信号通路。将进行T调节性细胞转移以实现耐受活性，并确定该活动的被动或传染性。相关性：稳态过程的失调与许多人类疾病有关，例如艾滋病，白血病，炎症碗疾病和自身免疫性疾病，例如1型糖尿病，多发性硬化症和关节炎。涉及T细胞稳态的过程，例如淋巴细胞激活，生存和死亡，目前正在密集研究中，因为它们与这些疾病有关。从这些研究中获得的信息将有助于开发移植过程中耐受性，增强肿瘤疫苗潜力和预防自身免疫性疾病的疗法。