Molecular basis of lymphocyte migration to the skin and mechanisms of acquisition of skin-migrating activity

淋巴细胞迁移到皮肤的分子基础和获得皮肤迁移活性的机制

基本信息

批准号：
17590433
负责人：
HIRATA Takako
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590433/
关键词：
T cells Adhesion molecules Selectins Sialomucins CD43 PSGL-1 Skin Leukocyte rolling

项目摘要

The skin is the principal physical barrier against pathogens and foreign antigens. Under steady-state conditions, some memory T cells reside in the skin, but upon infection, effector T cells are promptly recruited to the skin, and play a central role in the host defense against pathogens. T cell localization to the skin also plays a key role in the pathogenesis of many inflammatory skin diseases, such as contact dermatitis, atopic dermatitis and psoriasis. The recruitment of effector/memory T cells to the skin is mediated by P-and E-selectin expressed on dermal vascular endothelium. Although we showed previously that P-selectin glycoprotein ligand-1 (PSGL-1) on T cells functions as the major P-selectin ligand and also as an E-selectin ligand, the molecular nature of E-selectin ligands other than PSGL-1 remains unknown. In this research project, we showed that a 130-kDa glycoprotein was precipitated by an E-selectin-IgG chimera from mouse Th1 cells. The mAb 1B11, which recognizes the 13 … More 0-kDa glycoform of CD43, recognized and depleted the 130-kDa band in the E-selectin-IgG precipitate, confirming its identity as CD43. E-selectin-dependent cell rolling on CD43 was observed under flow conditions using a CD43-IgG chimera. To clarify the function of CD43 as an E-selectin ligand in vivo, we generated mice deficient in both PSGL-1 and CD43. In migration assays in which adoptively transferred cells migrate to inflamed skin P-and E-selectin-dependently, CD43 contributed significantly to PSGL-1-independent Th1 cell migration. In addition, in vivo-activated T cells from the draining lymph nodes of sensitized mice deficient in PSGL-1 and/or CD43 showed significantly decreased E-selectin-binding activity and migration efficiency, with T cells from double-deficient mice showing the most profound decrease. Collectively, these results demonstrate that the CD43 expressed on activated T cells functions as an E-selectin ligand and thereby mediates T cell migration to inflamed sites, in collaboration with PSGL-1. Less

皮肤是针对病原体和外国抗原的主要物理障碍。在稳态条件下，一些记忆T细胞位于皮肤中，但是感染后，效应T细胞迅速招募到皮肤，并在宿主防御病原体中发挥核心作用。 T细胞在皮肤上的定位在许多炎症性皮肤疾病的发病机理中也起着关键作用，例如接触性皮炎，特应性皮炎和牛皮癣。效应子/记忆T细胞募集到皮肤上是由皮肤血管森林上的P-and e-Selectin Express介导的。尽管我们先前证明了T细胞上的P-选择蛋白糖蛋白配体-1（PSGL-1）作为主要的P-选择蛋白配体以及E-纤维素配体，但除PSGL-1以外的E-选择蛋白配体的分子性质仍然是未知的。在该研究项目中，我们表明，由小鼠Th1细胞的E-选择蛋白-IGG嵌合体沉淀了130 kDa糖蛋白。 MAB 1B11识别CD43的13…更多0-kDa糖基型，在E-固定蛋白-IGG沉淀物中识别并耗尽了130 kDa频段，证实了其与CD43的身份。使用CD43-IGG嵌合体在流动条件下观察到CD43上的E-选择素依赖性细胞滚动。为了阐明CD43作为体内E-选择蛋白配体的功能，我们生成了缺乏PSGL-1和CD43的小鼠。在迁移分析中，适当转移的细胞迁移到发炎的皮肤P和E-选择蛋白依赖性依赖性，CD43对PSGL-1独立的Th1细胞迁移产生了显着贡献。此外，来自PSGL-1和/或CD43缺乏敏感小鼠的排水淋巴结的体内活化的T细胞显示出E-选择蛋白结合活性和迁移效率的显着降低，双重小鼠的T细胞显示出最深刻的下降。总的来说，这些结果表明，在活化的T细胞上表达的CD43充当E-选择蛋白配体，从而与PSGL-1合作介导T细胞迁移至发炎的位点。较少的