B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4.
The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor (BCR) and are associated with changes in the migration properties of B cells in response to chemokine gradients. The chemokine stromal cell-derived factor (SDF)-1alpha is thought to be one of the driving forces during those processes, as it is produced inside secondary lymphoid organs and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1alpha chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)gamma2 but independent of Ca2+ mobilization, suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1alpha receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1alpha migration is through PKC-dependent downregulation of CXCR4.
Guinamard
R
R
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021, USA.
Signoret
N
N
Ishiai
M
M
Marsh
M
M
Kurosaki
T
T
Ravetch
J V
JV
Masamichi
I
I
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology*; D002645:Chickens; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051966:Phospholipase C gamma; D011493:Protein Kinase C / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007527:Isoenzymes; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; D011493:Protein Kinase C; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium