Transforming Growth Factor beta in T-Cell Homeostasis and Tolerance

项目概述：t细胞稳态是维持外周血淋巴细胞池大小的重要过程。T细胞必须提供多样化的抗原识别库，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大，并在最初的病毒清除后收缩，为整个t细胞库腾出空间。这是一个严格调控的过程，因为淋巴细胞可用的空间是有限的。转化生长因子？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。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。TGF??表征-缺陷小鼠的自身免疫性疾病是由于T细胞自发激活以响应自身抗原识别，通过钙-钙调磷酸酶信号级联具有不适当的低阈值激活水平。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，并且减少钙调磷酸酶信号显著减轻其自身免疫性疾病。此外，已知没有TGF？介导免疫耐受的t调节细胞减少了。在此，我们建议研究TGF？参与t细胞稳态和自我耐受的调节。首先，我们将讨论TGF？1利用卵清蛋白特异性t细胞受体转基因TGF？1缺陷小鼠品系。过继转移和卵清蛋白活化研究将被使用。其次，我们将研究TGF?？及其在外周t细胞调控中的信号通路。将进行t调节性细胞转移以产生耐受活性，并确定该活性的被动或感染性。相关性：体内平衡过程的失调与许多人类疾病有关，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。涉及t细胞稳态的过程，如淋巴细胞活化、存活和死亡，由于它们与这些疾病的相关性，目前正在深入研究中。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性的治疗方法，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.