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

皮肤是抵抗病原体和外来抗原的主要物理屏障。在稳态条件下，一些记忆T细胞存在于皮肤中，但在感染时，效应T细胞被迅速招募到皮肤中，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病的发病机制中也起着关键作用，如接触性皮炎、特应性皮炎和牛皮癣。效应/记忆T细胞向皮肤的募集是由真皮血管内皮上表达的p -和e -选择素介导的。虽然我们之前已经证明T细胞上的p -选择素糖蛋白配体-1 （PSGL-1）既是p -选择素的主要配体，也是e -选择素的主要配体，但除了PSGL-1之外，e -选择素配体的分子性质仍然未知。在这个研究项目中，我们展示了一个来自小鼠Th1细胞的e - selection - igg嵌合体沉淀了一个130 kda的糖蛋白。mAb 1B11可以识别CD43的13…More 0-kDa糖型，识别并去除e -select - igg沉淀中的130-kDa带，确认其为CD43。使用CD43- igg嵌合体在流动条件下观察到依赖于CD43的e -选择细胞滚动。为了阐明CD43在体内作为e -选择素配体的功能，我们制造了PSGL-1和CD43都缺乏的小鼠。在迁移实验中，过继转移的细胞迁移到炎症皮肤依赖于p和e选择，CD43显著促进了psgl -1不依赖的Th1细胞迁移。此外，来自PSGL-1和/或CD43缺陷致敏小鼠引流淋巴结的体内活化T细胞的e-选择素结合活性和迁移效率显著降低，其中双缺陷小鼠的T细胞下降最为明显。总的来说，这些结果表明，活化T细胞上表达的CD43作为e -选择素配体的功能，从而介导T细胞迁移到炎症部位，与PSGL-1合作。少

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