Gene expression in memory CD4+T cells.

描述（由申请人提供）： 适当的T细胞功能对于抗感染免疫、有效疫苗和肿瘤免疫至关重要。 辅助性T细胞功能失调，特别是由CD 45 RO定义的记忆亚群，可能与诸如自身免疫性疾病、肿瘤监视失败和T细胞-皮肤T细胞淋巴瘤的明显恶性肿瘤等疾病相关。 目前，仍然缺乏对记忆T细胞在正常功能和疾病中的分子机制的理解，特别是在人类中。焦点基因是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细胞活化中起重要作用，并影响T细胞对抗原应答的能力。CTLA-4与共刺激分子137-1和137-2结合，并且在结构上与CD 28相关。在缺乏CTLA-4的情况下，存在严重的免疫失调，伴随不受控制的T细胞淋巴增殖。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。 当刺激记忆性CD 4 T细胞时，与初始CD 4 T细胞相比，CTLA-4的表达显示出显著增加。 这些发现支持初始和记忆T细胞之间CTLA-4表达的差异调节。 鉴于CTLA-4在控制T细胞功能中的重要作用，CTLA-4的精确表达在免疫应答中具有关键意义。 该提案描述了研究CTLA-4基因表达调控的实验。 具体而言，目的将是：1）研究CTLA-4启动子的转录调控，以及2）研究初始T细胞向记忆T细胞分化期间CTLA-4表达的调控。 了解CTLA-4差异表达的调控机制，可为设计调控CTLA-4表达的治疗方法以控制炎症性自身免疫性疾病的免疫应答和开发疫苗提供参考。

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.