51. Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells.
- Author
-
Phillips R and Ager A
- Subjects
- Adenosine Diphosphate Ribose metabolism, Animals, Cells, Cultured drug effects, Chemokine CCL19, Chemokine CCL21, Chemokine CXCL12, Chemokines, CC pharmacology, Chemokines, CC physiology, Chemokines, CXC biosynthesis, Chemokines, CXC genetics, Chemokines, CXC pharmacology, Chemotaxis drug effects, Endothelium cytology, Enzyme-Linked Immunosorbent Assay, GTP-Binding Protein alpha Subunits, Gi-Go drug effects, GTP-Binding Protein alpha Subunits, Gi-Go physiology, Humans, Mice, RNA, Messenger biosynthesis, Rats, Receptors, CXCR4 antagonists & inhibitors, Receptors, Chemokine drug effects, Receptors, Chemokine physiology, Chemokines, CXC physiology, Lymph Nodes cytology, Pertussis Toxin, T-Lymphocytes drug effects, Virulence Factors, Bordetella pharmacology
- Abstract
In this study we examined the role of chemokines in regulating T lymphocyte transmigration across the lining high endothelial cells (HEC) of high endothelial venules (HEV). The roles played by CCL21 (SLC), CCL19 (MIP-3 beta, ELC) and CXCL12 (SDF-1) were assessed using an in vitro transendothelial migration culture system, which constitutively supports high levels of lymphocyte transmigration. We determined that transmigration of T lymphocytes across HEC is inhibitable by treatment of the T lymphocytes with pertussis toxin (PTX) (80% inhibition). This was attributed to blockade of Gi-protein coupled receptors of T lymphocytes, since a non-ADP-ribosylating form of PTX had no significant effect on transendothelial migration. Inhibition of Gi-protein-coupled receptors on the endothelium had no effect on T cell transmigration. Treatment of T lymphocytes with a desensitizing concentration of CXCL12 caused a 60% reduction in T lymphocyte migration across HEC, and the CXCR4 antagonist SDF-1P2G reduced transmigration by 40%. Desensitizing concentrations of CCL21 and CCL19 had no significant effects on T lymphocyte transendothelial migration. Homologous desensitization of T lymphocytes to each chemokine was confirmed in a transwell migration assay. An approximately 3-kb mRNA corresponding to rat SDF-1 beta was constitutively expressed in HEC and cell surface CXCL12 was detectable by enzyme-linked immunosorbent assay. Together, these findings support a pivotal role for HEC-expressed CXCL12 and its receptor on T cells in the regulation of T lymphocyte homing to lymph nodes.
- Published
- 2002
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