Transforming Growth Factor beta in T-Cell Homeostasis and Tolerance

描述（由申请人提供）：项目概述：T细胞稳态是维持外周淋巴细胞池大小的重要过程。T细胞必须提供多样的抗原识别库，以有效地识别和摧毁它们遇到的病原体。抗原特异性T细胞库在病毒感染期间扩增，并在初始病毒清除后收缩，为整个T细胞库腾出空间。这是一个严格调控的过程，因为淋巴细胞可用的空间有限。转化生长因子？需要信号传导来预防自身免疫疾病和T细胞稳态失调。正常情况下，T细胞必须与自身MHC分子相互作用才能生存、维持和稳态扩增，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。转化生长因子的表征-缺陷型小鼠揭示了它们的自身免疫性疾病是由于它们的T细胞响应于自身抗原识别而自发活化引起的，所述自发活化是通过钙-钙调磷酸酶信号级联而具有不适当的低活化阈值水平。消除T细胞或其自身抗原识别足以预防这些小鼠中的自身免疫性疾病，并且减少钙调磷酸酶信号传导大大减弱其自身免疫性疾病。此外，它是已知的，没有TGF？这表明调节免疫耐受的T细胞减少了。在这里，我们建议调查的机制和过程中的作用，TGF？在调节T细胞稳态和自身耐受性方面。首先，我们将讨论如何TGF？1调节T细胞池的大小使用卵清蛋白特异性T细胞受体转基因TGF？1-缺陷小鼠品系。将使用连续转移和卵清蛋白活化研究。其次，我们将研究TGF？及其在外周T细胞调节中的信号通路。将进行T调节细胞转移以实现耐受化活性，并确定该活性的被动或感染性质。相关性：体内平衡过程的失调与许多人类疾病如艾滋病、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有关。涉及T细胞稳态的过程，如淋巴细胞活化，存活和死亡，目前正在深入研究，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期间诱导耐受的疗法，增强肿瘤疫苗的潜力，以及预防自身免疫性疾病。

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.