Chemokines and chemokine receptors: here, there, and everywhere

Comment on Hou et al, page 3488; and Paoletti et al, page 3405

In this issue of Blood, we explore two remarkable examples of chemokines and chemokine receptors taking part in unexpected roles and in unusual circumstances.

In the first featured publication, Hou and colleagues identify a chemokine receptor in an unexpected role as a marker for hematopoietic stem cell differentiation. Although its function in this situation is not yet clear, Hou and colleagues have identified a novel myeloid/lymphoid precursor cell based on the absence of CXCR4, a chemokine receptor required for B-cell development and hematopoietic stem cell engraftment. This minor cell population (CD34⁺ CD19⁺ CXCR4^-)responds to culture conditions promoting B-lymphocyte development by becoming CD34^-, CXCR4⁺, and kappa/lambda⁺ (see figure). These same cells respond to myeloid growth promoting conditions by forming granulocyte-macrophage, erythroid, and mixed myeloid colonies in standard methylcellulose assays. Overall, these results suggest that lymphoid/myeloid division may have some internal flexibility and branching points, with at least one branching point defined by the presence/absence of the chemokine receptor CXCR4.

In a second manuscript, Paoletti and colleagues demonstrate an unusual circumstance for chemokines and what on first pass might seem to be a counterintuitive finding, specifically, the positive impact of unrelated, nonagonist chemokines on the triggering of the receptor CC-chemokine receptor 7 (CCR7). The authors demonstrate that a wide variety of otherwise unrelated chemokines serve to reduce the signaling threshold and otherwise amplify responses observed for the CCR7 agonists secondary lymphoid tissue chemokine (SLC) and EBI1 (Epstein-Barr–induced 1) ligand chemokine (ELC). The authors suggest a mechanism involving formation of multimolecular complexes among the nonagonist chemokines and the selective agonist chemokines that results in a means of signal amplification. This mechanism implies that a chemokine-rich environment, rather than a simple gradient of 1 or 2 specific agonists, may have more of an overall impact on cell signaling in vivo. Given that any inflammatory response in vivo will involve a chemokine-rich environment, this finding has potential mechanistic implications worthy of significant consideration. ▪