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


CONCLUSIONS
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.
Honczarenko
Marek
M
Joint Program in Transfusion Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Glodek
Aleksandra M
AM
Swierkowski
Marcin
M
Na
Il-Kang
IK
Silberstein
Leslie E
LE
D001402:B-Lymphocytes / Q000502:physiology*; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000502:physiology; D002633:Chemotaxis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D010766:Phosphorylation; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C515460:CCL19 protein, human; C515478:CCL21 protein, human; C106311:CCR6 protein, human; C515370:CCR7 protein, human; C095085:CXCR5 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D007075:Immunoglobulin M; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases