CXCR7 Regulates Retention of Splenic Marginal Zone B Cells and Availability of SDF-1/CXCL12

Abstract 3902

CXCR7 is a newly discovered receptor for the chemokines I-TAC/CXCL11 and SDF-1/CXCL12. Overexpression of CXCR7 in certain tumors has been associated with increased activities of adhesion, invasion and survival. CXCR7 has thus been investigated as a potential chemotherapeutic target in the treatment of metastatic cancers. Our analyses of murine B cell lymphomas revealed that marginal zone B (MZB) cell lymphomas expressed higher levels of CXCR7 than other types of lymphomas. This prompted us to investigate the expression and function of CXCR7 in normal B cells. In this report, we demonstrate that normal MZB cells expressed the highest level of CXCR7 among all B cell subsets. This pattern of expression was consistent with gene profiling studies using cDNA microarrays. Injection of mice with CCX754 or CCX771, a specific blocker of CXCR7, resulted in a significant reduction of MZB cells in the spleen. Immunohistological analyses revealed disrupted integrity and reduced size of the MZ in spleens of CCX754-treated mice. In addition, CCX754 significantly blocked internalization of CXCR7 resulting in an increase of CXCR7 expression on MZB cells but not follicular B cells. This indicates that CXCR7 constantly removes its ligands from the extracellular environment. Taking together, our data suggest that CXCR7 controls CXCL12 availability influencing MZB cell retention in the spleen.