CD1-RESTRICTED T CELL RESPONSE IN ATHEROSCLEROSIS

动脉粥样硬化中 CD1 限制的 T 细胞反应

• 批准号: 6744661
• 负责人: Yong-Jian Geng
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744661
• 关键词: CD1; RESTRICTED; CELL; RESPONSE; ATHEROSCLEROSIS

DESCRIPTION (provided by applicant): CD1 is a membrane protein with structural and functional similarities to the MHC molecules, restricting presentation of hydrophobic or lipid antigens to T cells or NK T cells. Unlike the MHC class I and II molecules, CD1 acts as a restricting factor in a nonpolymorphic manner. Altered lipid metabolisms occur in atherosclerosis, leading to accumulation of chemically modified lipids in the arterial wall where T lymphocytes and macrophages are accumulating. It is likely that the immune cells are exposed to the atherogenic lipid antigens and become activated. Preliminary data from our studies on cultured cells have shown that treatment with certain lipids can induce expression of CD1 in vascular smooth muscle cells. This raises the possibility that CD1-positive smooth muscle cells may behave like dendritic cells and present lipid antigens to CD1-restricted T cells during the development of atherosclerosis. The central hypothesis is that loading with atherogenic lipids can enhance expression of CD1 proteins in the progenitors of vascular smooth muscle cells (SMC), which in turn act as antigen presenting cells capable of presenting the lipid antigens to T or NK T cells. Specific Aim 1 is to determine whether expression of CD1 is associated with differentiation of embryonic stem cells into vascular SMC; Specific Aim 2 to determine whether cytokines or growth factors such as interleukin-4 and monocyte colony stimulating factor (M-CSF) can synergize with lipids to induce expression of CD1 in vascular SMC progenitors as well as mature adult SMC; Specific Aim 3 to determine whether CD1 positive, lipid-loaded human SMC progenitors or ESC-derived SMC present CD1-restricted lipid antigens to T or NK T cells. Human embryonic stem cell lines will be used to generate SMC progenitors and produce stable cell lines which over-express CD1. Unique 3D culture system and T cell-human ESC/SMC co-cultures will be established. Fulfillment of the above objectives will provide novel mechanisms by which lipid antigens activate immune cells and cause inflammation in the arteries with atherosclerosis.

描述（由申请人提供）：CD1是一种膜蛋白，其结构和功能与MHC分子相似，限制疏水或脂质抗原向T细胞或NK T细胞的呈递。与MHC I类和II类分子不同，CD1以非多态性的方式作为限制因子。动脉粥样硬化中脂质代谢发生改变，导致化学修饰的脂质在T淋巴细胞和巨噬细胞积聚的动脉壁中积累。这可能是免疫细胞暴露于致动脉粥样硬化脂质抗原并被激活。我们对培养细胞的研究的初步数据表明，用某些脂质处理可以诱导血管平滑肌细胞中CD1的表达。这提出了一种可能性，即在动脉粥样硬化的发展过程中，cd1阳性的平滑肌细胞可能表现得像树突状细胞一样，向cd1限制性T细胞呈递脂质抗原。中心假设是，装载致动脉粥样硬化性脂质可以增强血管平滑肌细胞（SMC）祖细胞中CD1蛋白的表达，而血管平滑肌细胞反过来又作为抗原呈递细胞，能够将脂质抗原呈递给T或NK T细胞。特异性目的1是确定CD1的表达是否与胚胎干细胞向血管SMC的分化有关；特异性目的2：确定细胞因子或生长因子如白细胞介素-4和单核细胞集落刺激因子（M-CSF）是否能与脂质协同诱导血管SMC祖细胞和成熟成人SMC中CD1的表达；特异性目的3确定CD1阳性、脂质负载的人SMC祖细胞或esc来源的SMC是否向T细胞或NK T细胞提供CD1限制性脂质抗原。人类胚胎干细胞系将用于产生SMC祖细胞，并产生稳定的过表达CD1的细胞系。建立独特的3D培养体系和T细胞-人ESC/SMC共培养。上述目标的实现将提供脂质抗原激活免疫细胞并引起动脉粥样硬化炎症的新机制。