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: 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
• 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

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细胞稳态是维持周围淋巴细胞池的重要过程 尺寸。 T细胞必须提供多种抗原识别的曲目，以有效地识别和破坏 他们遇到的病原体。抗原特异性的T细胞池在病毒感染期间扩展，为 在初始病毒清除后收缩，为整个T细胞曲目腾出空间。这是一个紧密的 受调节过程，因为可用于淋巴细胞的空间受到限制。转化生长因子（3 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，维护和稳态扩张，但 在某些病理条件下，这种相互作用导致T细胞的不适当激活导致 自身免疫性疾病。 TGF01缺陷小鼠的表征揭示了它们的自身免疫性疾病 通过具有自发抗原识别的T细胞自发激活的结果 通过钙 - 钙调神经蛋白信号级联反应不适当的低阈值激活水平。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弱其自身免疫性疾病。另外，众所周知 没有TGF（3信号传导较少的T调节细胞，介导免疫耐受性的细胞。在这里我们 建议研究TGFP在调节T细胞中作用的机制和过程 体内平衡和自我耐受。首先，我们将通过使用一个 椭圆蛋白特异性T细胞受体转基因TGF（31缺陷菌株。收养转移和 将使用椭圆蛋白激活研究。其次，我们将研究TGF的作用（31及其信号传导 周围T细胞调节中的途径。 T调节细胞转移以实现耐受活性的影响 该活动的被动或传染性将被确定。 相关性：稳态过程的失调与许多人类疾病有关 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，多种 硬化和关节炎。参与T细胞稳态涉及的过程，例如淋巴细胞激活，生存和 由于与这些疾病的相关性，目前正在接受密集研究。信息 从这些研究中获得将有助于开发诱导耐受性的疗法 移植，以增强肿瘤疫苗的潜力和预防自身免疫性疾病。