Transforming Growth Factor beta in T-Cell Homeostasis and Tolerance

项目摘要：T细胞动态平衡是维持外周淋巴细胞池的基本过程 尺码。T细胞必须提供不同的抗原识别能力，才能有效识别和破坏 他们遇到的病原体。抗原特异性T细胞池在病毒感染期间扩大，并 在最初的病毒清除后感染，为整个T细胞谱系腾出空间。这是一个紧密的 由于可供淋巴细胞使用的空间有限，这是一种受调控的过程。转化生长因子(3 信号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、维持和自我平衡扩张，但 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，从而导致 自身免疫性疾病。TGF01缺陷小鼠的特征揭示了它们的自身免疫性疾病 他们的T细胞自发激活，以响应自身抗原识别的结果 钙-钙调神经磷酸酶信号通路激活阈值水平过低。淘汰 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，以及 减少钙调神经磷酸酶信号可以显著减轻他们的自身免疫性疾病。此外，众所周知， 没有转化生长因子(3)信号，T调节细胞就会减少，T调节细胞就会介导免疫耐受。在这里我们 建议研究TGFp在T细胞调节中的作用机制和过程 动态平衡和自我容忍。首先，我们将讨论TGF01如何使用一个 卵清蛋白特异性T细胞受体转基因转化生长因子(31缺陷小鼠品系。收养转让和 将使用卵清蛋白激活研究。其次，我们将研究转化生长因子(31)的作用及其信号转导 外周T细胞调节的途径。将进行T-调节性细胞转移以影响耐受活动 而这种活动的被动或传染性将被确定。 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 硬化症和关节炎。参与T细胞动态平衡的过程，如淋巴细胞激活、存活和 由于死亡与这些疾病有关，目前正在对其进行深入研究。这些信息 从这些研究中获得的结果将有助于开发诱导耐受的治疗方法 移植，以增强肿瘤疫苗潜力，并用于预防自身免疫性疾病。

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.