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6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the
J J Campbell1, E P Bowman, K Murphy
1Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University Medical School, Stanford, California 94305, USA. jcampbel@cmgm.stanford.edu
Insights
Secondary lymphoid-tissue chemokine (SLC) binds to CCR7, mediating lymphocyte homing. This chemokine and MIP-3beta attract key lymphocyte populations, suggesting a role in immune cell recirculation.
Area of Science:
- Immunology
- Cell Biology
Background:
- High endothelial venules express secondary lymphoid-tissue chemokine (SLC), crucial for lymphocyte homing to lymph nodes.
- Lymphocyte recirculation is vital for immune surveillance and response.
Purpose of the Study:
- To investigate the function of 6-C-kine/secondary lymphoid-tissue chemokine (6CK/SLC) in lymphocyte trafficking.
- To identify the specific receptor(s) for 6CK/SLC on circulating lymphocytes.
Main Methods:
- Assessing the effect of 6CK/SLC on lymphocyte adhesion under physiological shear conditions.
- Investigating the interaction of 6CK/SLC with known chemokine receptors, particularly CCR7.
- Analyzing the chemotactic responses of different lymphocyte subsets to 6CK/SLC and MIP-3beta.
Main Results:
- 6CK/SLC induces rapid, integrin-dependent arrest of rolling lymphocytes.
- 6CK/SLC is a potent agonist for the CCR7 receptor, also known as EBI-1 or BLR-2.
- Both 6CK/SLC and MIP-3beta attract naive and memory T cells and B cells, but not NK cells.
- Desensitization to MIP-3beta impairs lymphocyte chemotaxis to 6CK/SLC, indicating shared signaling pathways via CCR7.
- 6CK/SLC competes with MIP-3beta for binding to lymphocytes.
Conclusions:
- The majority of circulating lymphocytes utilize the CCR7 receptor to respond to both 6CK/SLC and MIP-3beta.
- These chemokines and their receptor CCR7 are likely key mediators of lymphocyte recirculation in vivo.
- Findings elucidate the molecular mechanisms governing lymphocyte homing and immune cell trafficking.
Abstract:
The beta chemokine known as 6-C-kine, secondary lymphoid-tissue chemokine (SLC), TCA4, or Exodus-2 (herein referred to as 6CK/SLC) can trigger rapid integrin-dependent arrest of lymphocytes rolling under physiological shear and is highly expressed by high endothelial venules, specialized vessels involved in lymphocyte homing from the blood into lymph nodes and Peyer's patches. We show that 6CK/SLC is an agonist for the lymphocyte chemoattractant receptor, CCR7 (EBI-1, BLR-2), previously described as a receptor for the related beta chemokine MIP-3beta (ELC or Exodus-3). Moreover, 6CK/SLC and MIP-3beta attract the same major populations of circulating lymphocytes, including naive and memory T cells > B cells (but not natural killer cells); desensitization to MIP-3beta inhibits lymphocyte chemotaxis to 6CK/SLC but not to the alpha chemokine SDF-1 (stromal cell-derived factor); and 6CK/SLC competes for MIP-3beta binding to resting mouse lymphocytes. The findings suggest that the majority of circulating lymphocytes respond to 6CK/SLC and MIP-3beta in large part through their common receptor CCR7 and that these molecules may be important mediators of physiological lymphocyte recirculation in vivo.