CD1-RESTRICTED T CELL RESPONSE IN ATHEROSCLEROSIS

描述(申请人提供)：CD1是一种膜蛋白，在结构和功能上与MHC分子相似，限制疏水性或脂类抗原呈递给T细胞或NK T细胞。与MHC I类和II类分子不同，CD1以非多态的方式发挥限制因子的作用。动脉粥样硬化时脂类代谢发生改变，导致化学修饰的脂类在动脉壁中积累，在那里T淋巴细胞和巨噬细胞正在聚集。免疫细胞很可能暴露在致动脉粥样硬化的脂类抗原中并被激活。我们对培养细胞的初步研究数据表明，某些脂质处理可以诱导血管平滑肌细胞CD1的表达。这增加了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为树突状细胞，并向CD1限制性T细胞呈递脂质抗原的可能性。中心假设是，负载致动脉粥样硬化脂类可以增强CD1蛋白在血管平滑肌细胞(SMC)前体细胞中的表达，而SMC作为抗原提呈细胞，能够将脂类抗原递送给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是确定细胞因子或生长因子如白介素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前体细胞和成熟成人SMC表达CD1；特异性目的3确定CD1阳性、脂质负载的人SMC前体细胞或ESC来源的SMC是否将CD1限制性的脂类抗原递给T或NK T细胞。人类胚胎干细胞株将被用来产生SMC前体细胞，并产生稳定的过表达CD1的细胞系。将建立独特的三维培养体系和T细胞-人ESC/SMC共培养体系。上述目标的实现将为脂质抗原激活免疫细胞并导致动脉粥样硬化的动脉炎症提供新的机制。

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.