Kupffer cell mediated deletion of activated CD8+ T cells

库普弗细胞介导的活化 CD8 T 细胞的缺失

• 批准号: 6812607
• 负责人: WAJAHAT Zafar MEHAL
• 金额: $ 8.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812607
• 关键词: CD95 molecule; Kupffer' s cell; MHC class I antigen; antigen presentation; apoptosis; cell adhesion molecules; cell cell interaction; cell growth regulation; cytotoxic T lymphocyte; genetically modified animals; indoleamine; laboratory mouse; lectin; leukocyte activation /transformation; ligands; tryptophan 2,3 dioxygenase; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): The immune response in the liver is frequently sub-optimal. Clinical examples of this are infection with hepatitis B and C viruses, as well as tolerance to oral and alloantigens. We are interested in the fate of activated CD8+ T cells after they have entered the liver and have demonstrated that i) the liver retains activated CD8+ T cells that enter it, even in the absence of specific peptide ii) the retained cells are in physical contact with Kupffer ceils (KC) and iii) undergo apoptosis. Between events i and iii very little is known about the retained CD8+ T cells. In the preliminary data generated in the first two years of the KO8 award we show that a) activated CD8+ T cells on entering the liver undergo approximately seven fold expansion over 48 hours b) this is followed by a gradual decrease over the next 5 days due to intrahepatic apoptosis c) the presence of specific peptide results in significant reduction in the retained CD8+ T cell pool due to enhanced apoptosis d) in the absence of KC, specific peptide does not results in reduction in the activated CD8+ T cell population. These results demonstrate that KC are required for antigen induced deletion of intrahepatic activated CD8+ T cells, and are consistent with two hypothesis: Hypothesis A: Antigen presentation by KC is responsible for antigen induced deletion of intraheptic CD8+ T cells. Hypothesis B: Antigen presentation on non-KC is responsible for antigen induced deletion of intrahepatic CD8+ T cells, but KC have an important role in delivering the apoptotic signal. Specific aim 1: Determine if KC specific inhibition of class I MHC processing in-vivo blocks apoptosis of intrahepatic CD8+ T cells. Specific aims 2a) Determine if antigen presentation by KC to activated CD8+ T cells in-vitro results in CD8+ T cell apoptosis. 2b) Determine if Kupffer cell ICAM-1, CD95-L, indoleamine dioxygenase and galectin-1 are important in the firm adhesion and apoptosis of CD8+ T cells. These aims will be achieved by using transgenic mice in which MHC class I presentation is inhibited in KC, and by developing in-vitro systems in which the role of the molecules in specific aim 2b in KC mediated apoptosis is tested.

描述（由申请人提供）： 肝脏的免疫反应常常不是最佳的。临床例子包括乙型肝炎和丙型肝炎病毒感染，以及对口腔和同种异体抗原的耐受。我们对激活的 CD8+ T 细胞进入肝脏后的命运感兴趣，并证明 i) 即使没有特定肽，肝脏仍保留进入其中的激活的 CD8+ T 细胞 ii) 保留的细胞处于物理接触状态库普弗细胞 (KC) 和 iii) 发生细胞凋亡。在事件 i 和 iii 之间，人们对保留的 CD8+ T 细胞知之甚少。在 KO8 奖项的前两年生成的初步数据中，我们表明：a) 激活的 CD8+ T 细胞进入肝脏后，在 48 小时内经历大约七倍的扩增 b) 随后在接下来的 5 天内逐渐减少，因为c) 由于细胞凋亡增强，特定肽的存在导致保留的 CD8+ T 细胞库显着减少 d) 在 KC 不存在的情况下，特定肽不会导致激活的 CD8+ T 细胞群减少。这些结果表明，KC 是抗原诱导的肝内活化 CD8+ T 细胞缺失所必需的，并且与两个假设一致： 假设 A：KC 的抗原呈递负责抗原诱导的肝内 CD8+ T 细胞缺失。假设 B：非 KC 上的抗原呈递导致抗原诱导的肝内 CD8+ T 细胞缺失，但 KC 在传递凋亡信号中发挥重要作用。 具体目标 1：确定 KC 对 I 类 MHC 体内加工的特异性抑制是否会阻止肝内 CD8+ T 细胞的凋亡。 具体目标 2a) 确定体外 KC 向活化的 CD8+ T 细胞呈递抗原是否会导致 CD8+ T 细胞凋亡。 2b) 确定库普弗细胞 ICAM-1、CD95-L、吲哚胺双加氧酶和半乳糖凝集素-1 在 CD8+ T 细胞的牢固粘附和凋亡中是否重要。 这些目标将通过使用转基因小鼠来实现，其中MHC I类呈递在KC中受到抑制，并通过开发体外系统来测试特定目标2b中的分子在KC介导的细胞凋亡中的作用。