| Research Abstract |
T-lymphocytes play principal roles in immune response. We studied the mechanism for site-specific recruitment of human helper T cell subsets with special attention to selectin, a family of cell adhesion molecules, which interact with specific carbohydrate counter-receptors. L-selectin, a member of the selectin family, is involved in the homing of naive helper T-lymphocytes into peripheral lymph nodes through high endothelial venules (HEV). We identified the carbohydrate ligand for L-selectin on HEV endothelial cells to be sialyl 6-sulfo Le^x, by generating specific antibodies, and by the reconstitution of functional L-selectin ligand by transfection of cDNAs for α1, 3 fucosyltransferase VII and GlcNAcβ : 6-Ο-sulfotransferase. The same determinant was expressed on HEVs of Peyer's patches and appendices, where it mediatesadhesion of the gut-homing helper memory T-lymphocytes bearing α_4β_7-integrin. A distinct subset of resting helper memory T-lymphocytes was also found to express sialyl
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6-sulfo Le^X. The subset strongly co-expressed PSGL-1 and CCR4, but not α_4β_7-integrin, indicating these cells are skin-homing helper memory T-lymphocytes, which home to the skin by interacting with E- and P-selectins on dermal endothelial cells. It is notable that the sialyl 6-sulfo Le^X is preferentially involved in routine homing process of various subsets of helper T-lymphocytes under non-inflammatory conditions.
In contrast, conventional sialyl Le^X was virtually not expressed on HEVs or on resting peripheral T-lymphocytes, but was prominently induced on lymphocytes upon TPA- or Con A-stimulation. This was accompanied by a remarkable transcriptional induction of fucosyltransferase VII, the rate-limiting enzyme for sialyl Le^X synthesis in leukocytes. Stimulation of peripheral T-lymphocytes abrogated the sialyl 6-sulfo Le^X expression, indicating that T-lymphocyte activation is accompanied by a switching of dominant molecular species of selectin ligands from sialyl 6-sulfo Le^X to conventional sialyl Le^X. We propose that sialyl 6-sulfo Le^X primarily mediates routine homing of resting T-lymphocytes, while conventional sialyl Le^X is preferentially involved in the recruitment of activated T-lymphocytes to inflammatory lesions. Selectin-binding activity of sialyl 6-sulfo Le^X on human lymphocytes was found to be regulated by a post-translational modification of its sialic acid moiety leading to the formation of "cyclicsialic acid", which would prevent excessive accumulation of lymphocytes at vascular beds in the routine homing process. Less
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