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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
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Molecular Immunology,
¶
Gene Expression Sciences, and
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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 Gi
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.
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