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

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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