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Chemoattractant (CXCL11)1
*
Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129; and
Immunology and Allergy Division, University Hospital, Lausanne, Switzerland.
Chemokine receptors are rapidly desensitized and internalized
following ligand binding, a process that attenuates receptor-mediated
responses. However, the physiological settings in which this process
occurs are not clear. Therefore, we examined the fate of CXCR3, a
chemokine receptor preferentially expressed on activated T cells
following contact with endothelial cells. By immunofluorescence
microscopy and flow cytometry, we found that CXCR3 was rapidly
internalized when T cells were incubated with IFN-
-activated human
saphenous vein endothelial cells (HSVEC), but not with resting HSVEC.
Similar results were obtained using human CXCR3-transfected murine
300-19 B cells. CXCR3 down-regulation was significantly more pronounced
when T cells were in contact with HSVEC than with their supernatants,
suggesting that CXCR3 ligands were efficiently displayed on the surface
of HSVEC. Using neutralizing mAbs to IFN-induced protein-10
(CXCL10), monokine induced by IFN- (CXCL9), and IFN-inducible
T cell 
chemoattractant (I-TAC; CXCL11), we found that even though
I-TAC was secreted from IFN--activated HSVEC to lower levels than
IFN-induced protein-10 or the monokine induced by IFN-, it was the
principal chemokine responsible for CXCR3 internalization. This
correlated with studies using recombinant chemokines, which revealed
that I-TAC was the most potent inducer of CXCR3 down-regulation and of
transendothelial migration. Known inhibitors of chemokine-induced
chemotaxis, such as pertussis toxin or wortmannin, did not reduce
ligand-induced internalization, suggesting that a distinct signal
transduction pathway mediates internalization. Our data demonstrate
that I-TAC is the physiological inducer of CXCR3 internalization and
suggest that chemokine receptor internalization occurs in physiological
settings, such as leukocyte contact with an activated
endothelium.
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