Control T helper (Th1) cell homing

控制 T 辅助细胞 (Th1) 细胞归巢

• 批准号: 6930549
• 负责人: Geoffrey S. Kansas
• 金额: $ 27.28万
• 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/6930549
• 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疾病的发展，以及同种异体移植排斥反应，部分取决于致病性T细胞到靶部位的归巢。尽管白细胞被招募到特定靶组织的基本分子机制是清楚的，但我们对这些过程如何在T细胞中被控制的知识仍存在重大空白。选择素是一类与碳水化合物结合的粘附分子，在白细胞运输中起着至关重要的作用。已知活化的T细胞，特别是辅助性T细胞（Th1）可以表达e -选择素和p -选择素的配体，这两种选择素基因家族的成员在内皮上表达，而这些碳水化合物配体的表达对于这些炎症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）很重要，而GT对于Th1细胞中选择素配体的形成至关重要。其中包括α 1,3酰基转移酶FucT-VII和0-聚糖分支酶core 2 β 1,6氨基葡萄糖转移酶1 （C2G1cNAcT-I）。然而，不同的GT在不同选择素的不同配体的生物合成中的确切作用尚不清楚，也不知道这些酶的表达是如何控制的。我们已经发现了在不同刺激下控制Th1细胞中不同GT表达的多种途径的证据。揭示这些不同的途径如何控制CD4细胞中参与选择素配体生物合成的多种相关GT的表达是本提案的总体主题。在第一个目标中，我们将继续确定在Th1细胞发育过程中选择配体生物合成中发挥作用的GT，并确定它们是否属于Th1归巢程序的一部分。在第二个目标中，我们将探索选择素配体表达与T细胞记忆之间的关系。在第三个目标中，我们将探索MAP激酶在控制Th1细胞中选择素配体形成中的作用。在第四个目标中，我们将开始揭示如何在Th1细胞中控制FucT-VII的表达的遗传基础。总的来说，这些研究将确定如何控制炎症性T细胞迁移，并揭示改善T细胞介导的自身免疫性和炎症性疾病的新靶点和途径。