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Departments of Immunology and Medicinal Chemistry, Berlex BioSciences, Richmond, CA 94804;
Laboratory of Immunology, National Institute on Aging, Baltimore, MD 21224;
Department of Surgery, Duke University Medical Center, Center for AIDS Research, Durham, NC 27710; and Departments of
§
Medicine and
¶
Medicine and Pathology and the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, PA 19104
The CXCR4 chemokine receptor has been shown to respond to the C-X-C
chemokine stromal-derived factor (SDF-1) and has recently been shown to
be an important coreceptor for HIV-1 infection. In the present paper we
have tested a number of human T lymphocyte cell lines, including
Jurkat, HUT78, CEM, and Sup-T1 for the presence of CXCR4 receptors. We
found that these T cell lines bind SDF-1
and SDF-1ß with high
affinity. The CXCR4 Ab 12G5 inhibited both SDF-1 binding and
HIV-1LAI-mediated fusion of CEM. Scatchard analysis
revealed the presence of approximately 150,000 SDF-1-binding sites
per cell with a Kd between 5 and 10 nM.
Cross-competition experiments using unlabeled SDF-1 and SDF-1ß
revealed that both chemokines are equally capable of displacing their
radiolabeled counterparts. Internalization studies with
[125]I-SDF-1 revealed that Jurkat cells internalized greater than
90% of the ligand by 2 h at 37°C. SDF-1 was also chemotactic
for Jurkat cells and caused an increase in the rate of extracellular
acidification that was half-maximal at 18 nM SDF-1 and could be
inhibited by pretreatment with the SDF-1 proteins, pertussis toxin, or
the Ab 12G5. Finally, SDF-1 also caused an increase in the cytosolic
Ca2+ concentration in Sup-T1 cells that was abolished by
preincubating the cells with pertussis toxin or PMA and inhibited by
the Ab 12G5. This molecular characterization of CXCR4 receptors should
prove useful in clarifying receptor interaction with SDF-1 proteins and
with HIV-1 glycoprotein, with the ultimate aim of targeting the viral
interaction for therapeutic intervention.
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