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CKß-11/Macrophage Inflammatory Protein-3ß/EBI1-Ligand Chemokine Is an Efficacious Chemoattractant for T and B Cells¹

Chang H. Kim^*,, Louis M. Pelus, John R. White^§, Edward Applebaum^¶, Kyung Johanson^|| and Hal E. Broxmeyer^2,*,

^* Departments of Microbiology/Immunology and Medicine and The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202; The Walther Cancer Institute, Indianapolis, IN 46208; Departments of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426; and Departments of ^§ Molecular Immunology, ^¶ Gene Expression Sciences, and ^|| Protein Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406

We examined the functional properties of CKß-11/MIP-3ß/ELC, a recently reported CC chemokine that specifically binds to a chemokine receptor, EBI1/BLR2/CCR7. CKß-11/MIP-3ß/ELC is distantly related to other CC and CXC chemokines in primary amino acid sequence structure. Recombinant human CKß-11/MIP-3ß/ELC expressed from a mammalian cell system showed potent chemotactic activity for T cells and B cells but not for granulocytes and monocytes. An optimal concentration of CKß-11/MIP-3ß/ELC attracted most input T cells within 3 h, a chemotactic activity comparable with that of stromal cell derived factor 1 (SDF-1), a highly efficacious CXC chemokine. CKß-11/MIP-3ß/ELC equally attracted naive CD45RA⁺ and memory type CD45RO⁺ T cells. CKß-11/MIP-3ß/ELC also strongly attracted both CD4⁺ and CD8⁺ T cells, but the attraction for CD4⁺ T cells was greater. CKß-11/MIP-3ß/ELC was also a more efficacious chemoattractant for B cells than MIP-1, a known B cell chemoattractant. CKß-11/MIP-3ß/ELC induced actin polymerization in lymphocytes, and chemotaxis was completely blocked by pertussis toxin showing its receptor, most likely EBI1/BLR2/CCR7, is coupled to a G_i protein. CKß-11/MIP-3ß/ELC induced calcium mobilization in lymphocytes, which could be desensitized by SDF-1, suggesting possible cross-regulation in their signaling. Human CKß-11/MIP-3ß/ELC attracted murine splenocytes suggesting functional conservation of CKß-11/MIP-3ß/ELC between human and mouse. The efficacy of chemoattraction by CKß-11/MIP-3ß/ELC and tissue expression of its mRNA suggest that CKß-11/MIP-3ß/ELC may be important in trafficking of T cells in thymus, and T cell and B cell migration to secondary lymphoid organs.