Gene expression in memory CD4+T cells.

描述(由申请人提供)： 适当的T细胞功能对抗感染免疫、有效疫苗和肿瘤免疫至关重要。辅助性T细胞功能失调，特别是CD45RO定义的记忆亚群，可能与自身免疫性疾病、肿瘤监测失败和T细胞-皮肤T细胞淋巴瘤的直接恶性有关。目前，对记忆T细胞在正常功能和疾病中的分子机制仍缺乏了解，尤其是在人类中。Focus的基因是CTLA-4，一种具有负调控特性的共刺激分子。该基因在T细胞活化过程中被诱导，在调节T细胞活化中发挥重要作用，并影响T细胞对抗原的应答能力。CTLA-4与共刺激分子137-1和137-2结合，在结构上与CD28相关。在缺乏CTLA-4的情况下，T细胞的淋巴增殖不受控制，存在严重的免疫失调。他们的初步研究证实，记忆T细胞中CTLA-4的表达水平增加了约7倍。当记忆性CD4T细胞受到刺激时，CTLA-4的表达较原始的CD4T细胞显著增加。这些发现支持了初始T细胞和记忆T细胞对CTLA-4表达的不同调控。鉴于CTLA-4在控制T细胞功能中的重要作用，CTLA-4的准确表达在免疫应答中具有重要意义。这项建议描述了研究CTLA-4基因表达调控的实验。本研究的目的是：1)研究CTLA-4启动子的转录调控；2)研究CTLA-4在幼稚T细胞向记忆T细胞分化过程中的表达调控。了解CTLA-4差异表达的调控机制可能为设计调控CTLA-4表达的治疗方法、控制炎症性自身免疫性疾病的免疫反应以及疫苗的研制提供新的思路。

DESCRIPTION (provided by applicant): Appropriate T cell function is critical to immunity against infections, effective vaccine and tumor immunity. Dysregulation of T helper cell function, particularly the memory subset as defined by CD45RO, may be associated with diseases such as autoimmune diseases, failure of tumor surveillance and frank malignancy of T cells-cutaneous T cell lymphoma. Presently, there remains a lack of understanding in the molecular mechanisms governing memory T cells in normal function and in disease, particularly in humans. The gene of focus is CTLA-4, a co-stimulatory molecule with negative regulatory properties. This gene is induced during T cell activation, plays an important role in regulating T cell activation and affects the ability of T cells to respond to antigen. CTLA-4 binds to co-stimulatory molecules 137-1 and 137-2, and is related to CD28 structurally. In the absence of CTLA-4, there is profound immune dysregulation with uncontrolled lymphoproliferation of T cells. Their preliminary studies confirmed an increased level of CTLA-4 expression in memory T cells by approximately 7-fold. When memory CD4 T cells are stimulated, the expression of CTLA-4 shows a marked increase in comparison to naive CD4 T cells. These findings support the differential regulation of CTLA-4 expression between naive and memory T cells. Given the important role of CTLA-4 in controlling T cell function, the precise expression of CTLA-4 has critical implications in the immune response. This proposal describes experiments to investigate the regulation of CTLA-4 gene expression. Specifically, the aims will be: 1) to study the transcriptional regulation of CTLA-4 promoter, and 2) to study the regulation of CTLA-4 expression during differentiation of naive T cells to memory T cells. Understanding the mechanism regulating the differential expression of CTLA-4 may provide insights for the design of therapy to modulate CTLA-4 expression for control of immune response in inflammatory autoimmune diseases and for the development of vaccines.