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Vol. 59, Issue 4, 707-715, April 2001
Chemoattractant Are Allotopic Ligands
for Human CXCR3: Differential Binding to Receptor States
Department of Immunology, Schering-Plough Research Institute,
Kenilworth, New Jersey
The human CXC chemokines IP-10 (10-kDa interferon-inducible protein),
MIG (monokine induced by human interferon-
), and I-TAC (interferon-inducible T cell 
chemoattractant) attract lymphocytes through activation of CXCR3. In the studies presented here, we examined
interaction of these chemokines with human CXCR3 expressed in
recombinant cells and human peripheral blood lymphocytes (PBL). IP-10,
MIG, and I-TAC were agonists in stimulating [35S]GTPS
binding in recombinant cell and PBL membranes but had no effect in the
absence of hCXCR3 expression. 125I-IP-10 and
125I-I-TAC bound hCXCR3 with high affinity, although the
125I-I-TAC Bmax value in
saturation bindings was 7- to 13-fold higher than that measured with
125I-IP-10. Coincubation with unlabeled chemokines
decreased 125I-IP-10 binding with a single discernible
affinity. However, with 125I-I-TAC, competition with IP-10
or MIG was incomplete, and multiple binding affinities were evident.
Moreover, in contrast to I-TAC, IP-10 and MIG binding IC50
values did not increase predictably with increased
125I-I-TAC concentration in competition bindings,
suggesting that these chemokines are noncompetitive (i.e., allotopic)
ligands. Uncoupling of hCXCR3 eliminated 125I-IP-10 binding
but only decreased 125I-I-TAC binding 30 to 80%,
indicating that unlike IP-10, I-TAC binds with high affinity to
uncoupled (R) and coupled (R*) hCXCR3. To
examine chemokine binding to R*, we tested the effect of
anti-hCXCR3 antibody on I-TAC- and IP-10-stimulated [35S]GTPS binding. The antibody attenuated
[35S]GTPS binding in response to IP-10 but
not to I-TAC, suggesting that the two chemokines bind differently to
R*. Moreover, increased occupancy of R* with a
>75-fold increase in 125I -IP-10 concentration
did not increase the I-TAC binding IC50 value,
and I-TAC increased the dissociation rate of
125I-IP-10. From these data, we conclude that the
binding of IP-10 and I-TAC to the R* state of hCXCR3 is allotopic.
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