Developmental stage-specific shift in responsiveness to chemokines during human B-cell development

Exp Hematol. 2006 Aug;34(8):1093-100. doi: 10.1016/j.exphem.2006.05.013.

Abstract

Objectives: To better understand the role of chemokines during human B-cell development in bone marrow.

Methods: Differentiation stage-specific B cells (pro-B, pre-B, immature, and mature) were analyzed for chemokine receptor expression and for migration to corresponding ligands. We also hypothesized that inflammatory conditions may cause the upregulation of certain chemokine receptors on early B cells, rendering them sensitive to extramedullary chemotactic cues. To test this hypothesis, we used human pre-B 697 cells to investigate whether various inflammatory agents could modify chemokine receptor expression and function.

Results: Chemotaxis to CXCL12 was observed for all B cell subsets. However, chemotactic responses to CCL19, CCL21, CXCL13, and CCL20 were limited to late-stage, IgM+ bone marrow B cells (immature B and mature B). Chemotactic responses to corresponding ligands correlated with the pattern of chemokine receptor expression. The expression of CCR7, however, was low on early (pro-B and pre-B) B cells and did not induce chemotaxis. Interestingly, both CCL19 and CCL21 could trigger ERK1/2 phosphorylation in early B cells. Exposure of pre-B 697 cells to TNF-alpha upregulated CCR7 and CXCR5 expression, whereas it had no effect on CCR6 surface expression. Correspondingly, TNF-alpha-stimulated pre-B cells chemotaxed towards CCL19 and CXCL13, in contrast to non-TNF-alpha-stimulated controls.

Conclusion: We postulate that CXCR5, CCR7, and CCR6 participate in bone marrow trafficking and/or bone marrow egress of late-stage B cells under steady-state conditions, whereas inflammation-induced expression of CCR7 and CXCR5 may facilitate early B-cell emigration out of the bone marrow and their positioning in secondary lymphoid organs.

MeSH terms

  • B-Lymphocytes / physiology*
  • Chemokine CCL19
  • Chemokine CCL21
  • Chemokines, CC / physiology
  • Chemotaxis
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Gene Expression Regulation
  • Hematopoiesis*
  • Humans
  • Immunoglobulin M / biosynthesis
  • Phosphorylation
  • Receptors, CCR6
  • Receptors, CCR7
  • Receptors, CXCR5
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / physiology*
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • CCL19 protein, human
  • CCL21 protein, human
  • CCR6 protein, human
  • CCR7 protein, human
  • CXCR5 protein, human
  • Chemokine CCL19
  • Chemokine CCL21
  • Chemokines, CC
  • Immunoglobulin M
  • Receptors, CCR6
  • Receptors, CCR7
  • Receptors, CXCR5
  • Receptors, Chemokine
  • Receptors, Cytokine
  • Tumor Necrosis Factor-alpha
  • Extracellular Signal-Regulated MAP Kinases