Abstract
The CXCL12–CXCR4 axis plays a key role in the retention of stem cells and progenitors in dedicated bone marrow niches. It is well-known that CXCR4 responsiveness in B lymphocytes decreases dramatically during the final stages of their development in the bone marrow. However, the molecular mechanism underlying this regulation and whether it plays a role in B-cell homeostasis remain unknown. In the present study, we show that the differentiation of pre-B cells into immature and mature B cells is accompanied by modifications to the relative expression of chemokine receptors, with a two-fold downregulation of CXCR4 and upregulation of CCR7. We demonstrate that expression of CCR7 in B cells is involved in the selective inactivation of CXCR4, and that mature B cells from CCR7−/− mice display higher responsiveness to CXCL12 and improved retention in the bone marrow. We also provide molecular evidence supporting a model in which upregulation of CCR7 favors the formation of CXCR4–CCR7 heteromers, wherein CXCR4 is selectively impaired in its ability to activate certain G-protein complexes. Collectively, our results demonstrate that CCR7 behaves as a novel selective endogenous allosteric modulator of CXCR4.
Highlights
G protein-coupled receptors (GPCRs) are a large family of receptor proteins that respond to a great range of extracellular stimuli
When analyzing the proportions of B cell subpopulations, we showed that the number of mature B cells is selectively increased in the bone marrow of CCR7-/- mice (Fig 2A, and S5 Fig) while the number of CD4+ or CD8+ cells remains similar in CCR7-/- and wild type mice (S6 Fig)
When analyzing B cell subpopulations, we found that the number of mature B cells remains unaffected while the number of Pre B cells decreases significantly, which results in a higher proportion of CCR7-/- mature B cells in the bone marrow of reconstituted mice
Summary
G protein-coupled receptors (GPCRs) are a large family of receptor proteins that respond to a great range of extracellular stimuli. They are involved in many physiological processes and are targeted by approximately 40% of all medicinal drugs [1]. When lymphopoiesis progress to more differentiated stages, B cells lose their responsiveness to CXCL12 despite the continuous expression of CXCR4 [12,13,14,15,9]. As CCR7 upregulation takes place in B cell populations known to display poor CXCR4 responsiveness, we investigated whether CCR7 could be involved in the inhibition of CXCR4 function
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