Control T helper (Th1) cell homing

控制 T 辅助细胞 (Th1) 细胞归巢

• 批准号: 6541660
• 负责人: Geoffrey S. Kansas
• 金额: $ 27.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541660
• 关键词: autoimmunity; cell line; cell migration; cellular immunity; clone cells; enzyme activity; flow cytometry; gene expression; gene targeting; genetically modified animals; glycosyltransferase; helper T lymphocyte; immunologic memory; inflammation; laboratory mouse; leukocyte adhesion molecules; microarray technology; mitogen activated protein kinase; protein biosynthesis; selectins

DESCRIPTION (provided by applicant): The development of T cell-mediated autoimmune and inflammatory disorders, as well as allograft rejection, depends in part on the homing of pathogenic T cells to the target site. Although the basic molecular mechanisms by which leukocytes are recruited to specific target tissues are clear, there are significant gaps in our knowledge regarding how these processes are controlled in T cells. Selectins are a family of carbohydrate-binding adhesion molecules well established to play a crucial role in leukocyte traffic. Activated T cells, particularly T helper 1 (Th1) cells, are known to express ligands for E-selectin and P-selectin, two members of the selectin gene family which are expressed on endothelium, and expression of these carbohydrate ligands is essential for recruitment of these inflammatory Th1 cells to sites of inflammation. We have shown that IL- 12 is important for the induction of certain glycosyltransferases (GT) that are crucial for the formation of selectin ligands in Th1 cells. Among these GT are the alpha1, 3 fucosyltransferase FucT-VII and the 0-glycan branching enzyme core 2 beta1, 6 glucosaminyltransferase 1 (C2G1cNAcT-I). However, the precise role of different GT in the biosynthesis of distinct ligands for different selectins is not clear, nor is it known how the expression of these enzymes is controlled. We have uncovered evidence for multiple pathways which control the expression of different GT in Th1 cells in response to different stimuli. Unraveling how these various pathways control the expression of the multiple relevant GT involved in selectin ligand biosynthesis in CD4 cells is the overall theme of this proposal. In the first aim, we will continue to identify GT which play a role in selectin ligand biosynthesis in developing Th1 cells and determine if they are part of a Th1 homing program. In the second aim, we will explore the relationship between selectin ligand expression and T cell memory. In the third aim, we will explore the role of MAP kinases in controlling selectin ligand formation in Th1 cells. In the fourth aim, we will begin to uncover the genetic basis for how expression of FucT-VII is controlled in Th1 cells. Collectively, these studies will determine how inflammatory T cell migration is controlled, and uncover new targets and pathways for amelioration of T cell-mediated autoimmune and inflammatory disorders.

描述（由申请人提供）：T 细胞介导的自身免疫和炎症性疾病以及同种异体移植排斥的发生部分取决于致病性 T 细胞归巢至靶位点。尽管白细胞被募集到特定靶组织的基本分子机制很清楚，但我们对 T 细胞如何控制这些过程的了解还存在很大差距。选择素是碳水化合物结合粘附分子家族，在白细胞运输中发挥着至关重要的作用。已知激活的 T 细胞，特别是辅助性 T 1 (Th1) 细胞表达 E-选择素和 P-选择素（在内皮上表达的选择素基因家族的两个成员）的配体，这些碳水化合物配体的表达对于将这些炎症 Th1 细胞募集到炎症部位至关重要。我们已经证明，IL-12 对于诱导某些糖基转移酶 (GT) 非常重要，而这些糖基转移酶对于 Th1 细胞中选择素配体的形成至关重要。这些 GT 包括 α1, 3 岩藻糖基转移酶 FucT-VII 和 0-聚糖分支酶核心 2 beta1, 6 葡萄糖胺基转移酶 1 (C2G1cNAcT-I)。然而，不同GT在不同选择素的不同配体生物合成中的确切作用尚不清楚，也不知道如何控制这些酶的表达。我们发现了多种途径的证据，这些途径控制 Th1 细胞中不同 GT 的表达以响应不同的刺激。揭示这些不同的途径如何控制参与 CD4 细胞中选择素配体生物合成的多个相关 GT 的表达是本提案的总体主题。第一个目标是，我们将继续鉴定在 Th1 细胞发育过程中选择素配体生物合成中发挥作用的 GT，并确定它们是否是 Th1 归巢程序的一部分。第二个目标是探索选择素配体表达与 T 细胞记忆之间的关系。第三个目标是探索 MAP 激酶在控制 Th1 细胞中选择素配体形成中的作用。第四个目标是，我们将开始揭示 Th1 细胞中如何控制 FucT-VII 表达的遗传基础。总的来说，这些研究将确定如何控制炎症 T 细胞迁移，并揭示改善 T 细胞介导的自身免疫和炎症性疾病的新靶点和途径。