CXCR7 influences the migration of B cells during maturation

Abstract

The atypical chemokine receptor CXCR7 binds the chemokines CXCL12 and CXCL11. The receptor is widely expressed and was shown to tune CXCR12-induced responses of CXCR4. Here, the function of CXCR7 was examined at late stages of human B-cell maturation, when B cells differentiate into Ab-secreting plasmablasts. We identified two populations of CXCR7 + cells in tonsillar lymphocytes, one being presumably memory potential contribution of the scavenger receptor in final B-cell maturation. On in vitro differentiating B cells, we found a marked inverse correlation between CXCR7 and CXCR5 cell surface levels, whereas expression of CXCR4 remained almost constant. Migration assays performed with tonsillar mononuclear cells or in vitro differentiated cells revealed that inhibition of CXCR7 markedly increases chemotaxis toward CXCL12, especially at late stages of B-cell maturation. Chemotaxis was attenuated in the presence of CXCR4 antagonists, confirming that migration is CXCR4 mediated. Our findings unequivocally demonstrate a novel role for CXCR7 in regulating the migration of plasmablasts during B-cell maturation.Keywords: Atypical chemokine receptor r B cells r CXCR4 r CXCR5 r CXCR7Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAfter birth, B lymphopoiesis occurs in the BM, where cells progress through pro-B cell and pre-B cell stages. By expression of a functional BCR, B cells acquire antigen specificity and enter the periphery as transitional immature B cells, eventually maturing into follicular or marginal zone B cells [1]. Follicular B cells circulateCorrespondence: Dr. Marcus Thelen e-mail: marcus.thelen@irb.usi.ch between lymphoid organs and form GCs within secondary lymphoid organs upon activation. The GC splits up into two histological distinct compartments, the dark zone, where B cells are tightly packed and proliferate, and the light zone. Within the GC, CXCL12 is preferentially expressed in the dark zone, whereas CXCL13, which is also expressed in the follicle, is mainly found in the light zone. B cells may modulate the surface expression of CXCR5 and move between the zones of the GC attracted by CXCL12 and CXCL13 [2]. Activated B cells can grow and differentiate into plasmablasts in extrafollicular foci or form GCs within follicles [3,4]. Within the GC, activated B cells can differentiate into memory or plasma C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 694-705 Cellular immune response 695 cells [5]. Cells expressing a BCR with high avidity for an antigen differentiate preferentially along the plasma cell pathway and this process might be regulated by expression of factors such as the B-lymphocyte maturation-induced-protein-1, BCL-6, and X-box binding protein-1 [6][7][8] or cytokines such as IL-6 or APRIL [3]. Others showed that Bcl-2, the cytokine IL-21, and SWAP-70, which functions in activation, homing, and class switching of B cells, and is strongly upregulated in GC B cel...

MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP‐70 signaling, and lymphocyte chemotaxis

“…Notwithstanding this possibility, the notion of a specific role for MIF/CXCR7 was further substantiated by the observation that MIF‐mediated B‐cell chemotaxis was similarly inhibited by the CXCR4 antagonist AMD3100, confirming prior results (14), whereas CXCL12‐mediated B‐cell chemotaxis was blocked by AMD3100 but not by anti‐CXCR7 antibody. The latter result was in contrast to prior data showing that antibody‐based CXCR7 blockade led to an increase in migration (29, 45). This discrepancy could be caused by the cell type used (primary murine splenic B cells) or antibody dose applied.…”

“…In addition, one study showed that CXCL12 signals through CXCR7 to promote T‐cell migration, an effect that was reduced by a CXCR7‐blocking antibody (19), whereas in another study, blockade of CXCR7 with a neutralizing antibody or the small‐molecule compound CCX733 showed no impact on CXCL12‐enhanced T‐cell chemotaxis (61). In B lymphocytes, Humpert et al (45) demonstrated that blocking CXCR7 in in vitro ‐differentiated cells enhances CXCR4‐dependent migration of B cells toward CXCL12, implicating CXCR7 in the migration of B cells during maturation. We found that targeting CXCR7 with a neutralizing antibody significantly inhibited splenic B‐cell chemotaxis in response to MIF, whereas CXCL12‐mediated chemotaxis of primary B cells was not affected.…”

“…To further address the biologic relevance of MIF/ CXCR7 binding, we used primary murine B cells and studied the role of CXCR7 in MIF-triggered ERK-MAPK and ZAP-70 signaling, as well as migration responses, as these activities have been associated with MIF in B cells (14). In addition, CXCR7 has been shown to play an indirect role in CXCL12/CXCR4-dependent B-cell migration (45).…”

Biased signaling pathways via CXCR3 control the development and function of CD4+ T cell subsets

“…In addition, the scavenging activity of the receptor is essential to prevent CXCR4 down-regulation, e.g., during migration of interneurons [44,45]. Recently, it was shown that ACKR3 expression on CXCR4 + plasma blasts licenses them to leave CXCL12-rich germinal centers [46]. Under inflammatory conditions when endothelial cells up-regulate ACKR3, the receptor promotes infiltration of leukocytes into the brain parenchyma through scavenging of perivascular CXCL12 at the basal site of brain blood microvessels [47].…”

Induction of Regulatory B-Cells by Mesenchymal Stem Cells is Affected by SDF-1α-CXCR7

“…Previous research has shown that human breast adipose-derived stem cells (HBASCs) transfected with CXCR4 can enhance the survival and quality of transplanted free fat tissues in nude mice [26]. CXCR7, an atypical chemokine receptor that binds CXCL12 and CXCL11 [27], has also been shown to associate with CXCR4 and regulate CXCR4/SDF-1-mediated processes, such as the migration of plasmablasts during B-cell maturation [28]. However, the CXCR7-mediated cellular responses to CXCL12 are still largely unknown.…”