CCR2: holding B cells back

Comment on Flaishon et al, page 933

In this issue, Flaishon et al describe a novel role for the chemokine receptor CCR2 and its ligand CCL2/JE in inhibiting the chemotactic response of immature B cells to the chemokine CXCL12/SDF-1.

Although best known for their chemoattractant properties, chemokines also modulate the cellular response to other chemokines. Flaishon and colleagues describe a role for the C-C chemokine receptor 2 (CCR2) and its ligand CCL2/JE in inhibiting the chemotactic response of immature B cells to the chemokine CXCL12/stromal cell–derived factor 1 (SDF-1). They show that CCR2-deficient immature mouse B cells have increased migratory capacity to CXCL12/SDF-1 in vitro and that pretreatment of CCR2-positive immature B cells with CCL2/JE decreases their responsiveness to CXCL12/SDF-1. Injected CCR2-deficient immature B cells also accumulated at higher levels in the lymph nodes of mice compared with wild-type B cells.

The precise mechanism of this heterologous desensitization mediated by CCR2 was not identified, but signaling cross talk was suggested. In particular, they showed that the expression level of the CXCL12/SDF-1 receptor CXCR4 and the calcium flux following CXCL12/SDF-1 binding were unaffected by CCL2/JE pretreatment, whereas there was decreased CXCL12/SDF-1–induced phosphoactivation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Inhibition of CXCR4 signaling by CCR2 ligands has also been seen in other cell types.¹  Besides its expression in immature B cells, CCR2 is also expressed in a subset of mature B-cell neoplasms.²  It has previously been shown that CCR5 binding can also induce heterologous desensitization to CXCL12/SDF-1 in immature human B cells,³  a finding that was also observed in T cells. It will be of interest to discover if the mechanisms of CXCR4 signaling inhibition are similar between these 2 receptors and whether they are operative in human B-cell tumors, nearly all of which respond to CXCL12/SDF-1.FIG1 

Heterologous desensitization in immature B cells provides further demonstration that chemokines can compete with each other in complex ways to influence leukocyte localization. The most obvious competitive mechanism is the differential temporal and spatial expression gradients for each chemokine. Given that most leukocytes express several chemokine receptors and that several chemokines bind to most receptors with varying affinities, modeling these interactions becomes dauntingly complex. The frequent autocrine expression of chemokines by the migrating cell itself may also dampen responses to exogenous chemokines. Feedback from downstream effects of chemokines can also negatively regulate chemotactic response as with T cells, where chemokines promote adhesion and cellular activation, which subsequently affects loss of chemotactic response to some but not other chemokines.⁴  Finally, the production of agonist and antagonist chemokines by ubiquitous human herpes viruses provides additional opportunities for chemokine competition in pathologic states. For most leukocytes, chemokine competition, including through heterologous desensitization, likely plays a dominant role in ultimately determining localization patterns.