Control T helper (Th1) cell homing

描述（由申请人提供）：T细胞介导的自身免疫性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。虽然白细胞被募集到特定靶组织的基本分子机制是清楚的，但关于这些过程如何在T细胞中控制，我们的知识存在重大差距。选择素是一个碳水化合物结合的粘附分子家族，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T辅助1（Th 1）细胞表达E-选择素和P-选择素的配体，这两个选择素基因家族的成员在内皮上表达，并且这些碳水化合物配体的表达对于将这些炎性Th 1细胞募集到炎症部位是必需的。我们已经表明，IL- 12是重要的诱导某些糖基转移酶（GT）是至关重要的选择素配体在Th 1细胞的形成。在这些GT中有α 1，3岩藻糖基转移酶FucT-VII和0-聚糖分支酶核心2 β 1，6葡糖胺基转移酶1（C2 G1 cNAcT-I）。然而，不同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，也不知道如何控制这些酶的表达。我们已经发现了多种途径的证据，这些途径控制不同GT在Th 1细胞中响应于不同刺激的表达。揭示这些不同的途径如何控制参与选择素配体在CD 4细胞中生物合成的多个相关GT的表达是本提案的总体主题。在第一个目标中，我们将继续鉴定GT在Th 1细胞发育中选择素配体生物合成中发挥作用，并确定它们是否是Th 1归巢程序的一部分。第二个目的是探讨选择素配体表达与T细胞记忆的关系。在第三个目标中，我们将探索MAP激酶在控制Th 1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FucT-VII在Th 1细胞中的表达是如何控制的遗传基础。总的来说，这些研究将确定如何控制炎性T细胞迁移，并揭示改善T细胞介导的自身免疫性和炎性疾病的新靶点和途径。

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.