We greatly appreciate the interest of O'Boyle et al. in our recent paper (1) and their contributions to the functional interaction of GPCR chemokine receptors (2). We definitely share the opinion that the interaction of chemokines, or in a broader perspective of GPCRs involved in migration, is of great importance to understand the pathophysiology of chronic inflammation and cancer, but also of physiological conditions like bone marrow cell homeostasis. In our lymphocyte experiments, we have no evidence so far for a CXCR3/CXCR4-heterodimer formation suggested by O’Boyle et al. However, recently Watts et al. investigated CXCR3/CXCR4-heterodimers in HEK293T cells (3). A small CXCR3 agonist, VUF10661, impaired binding of CXCL12 to CXCR4, a finding supporting O’Boyle’s data. The effects are explained by an allosteric interaction of CXCR4 and CXCR3 upon agonist binding. Moreover, Watts et al. (3) demonstrated a specific β-arrestin2 recruitment to CXCR3/CXCR4-heteromers. Interestingly, the CXCR4/CXCR7 heterodimer complex also recruits β-arrestin, resulting in preferential activation of β-arrestin–linked signaling pathways and in enhanced cell migration (4). A further study with T lymphocytes, however, showed that CXCR7 can both enhance and decrease CXCL12-mediated chemotaxis (5). This indicates that, apart from heterodimer formation, the final biological effect of multiple chemokines acting through their cognate GPCRs is dependent on the specific cell-type and its respective differentiation status–dependent signaling apparatus. Adding complexity, the finding that the lipid mediator S1P via S1PR3 is directly altering the phosphorylation status of CXCR4 further extends the scope not only to another family of migratory active GPCRs but moreover to physiological conditions (6). Despite their therapeutic potential, the development of chemokine modulatory drugs has declined. We think that studies like the ones discussed in this correspondence are of decisive importance to better understand interactions of multiple chemotactic factors, which in a temporal and spatial order affect the distribution and final destination of immune cells, and thus may finally support new immunotherapeutic approaches.

1
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Ogrissek
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Radeke
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2013
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3
Watts
A. O.
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van Lipzig
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Jaeger
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Seeber
R. M.
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van Zwam
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2013
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4
Décaillot
F. M.
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M. A.
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Lin
Y.
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Ray-Saha
S.
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Sakmar
T. P.
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Sachdev
P.
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2011
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CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration
.
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5
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A.
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K.
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Baleux
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Bachelerie
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Lagane
B.
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2009
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6
Walter
D. H.
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Rochwalsky
U.
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Reinhold
J.
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Seeger
F.
,
Aicher
A.
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C.
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I.
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Chun
J.
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Brinkmann
V.
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2007
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