CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow.
Leukocyte residence in lymphoid organs is controlled by a balance between retention and egress-promoting chemoattractants sensed by pertussis toxin (PTX)-sensitive Gαi protein-coupled receptors (GPCRs). Here, we use two-photon intravital microscopy to show that immature B cell retention within bone marrow (BM) was strictly dependent on amoeboid motility mediated by CXCR4 and CXCL12 and by α4β1 integrin-mediated adhesion to VCAM-1. However, B lineage cell egress from BM is independent of PTX-sensitive GPCR signaling. B lineage cells expressing PTX rapidly exited BM even though their motility within BM parenchyma was significantly reduced. Our experiments reveal that when immature B cells are near BM sinusoids their motility is reduced, their morphology is predominantly rounded, and cells reverse transmigrate across sinusoidal endothelium in a largely nonamoeboid manner. Immature B cell egress from BM was dependent on a twofold CXCR4 down-regulation that was antagonized by antigen-induced BCR signaling. This passive mode of cell egress from BM also contributes significantly to the export of other hematopoietic cells, including granulocytes, monocytes, and NK cells, and is reminiscent of erythrocyte egress.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Thomas C
TC
Beck
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Ana Cordeiro
AC
Gomes
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
Jason G
JG
Cyster
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 joao.pereira@yale.edu.
João P
JP
Pereira
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage; D002465:Cell Movement; D048430:Cell Shape; D015536:Down-Regulation; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C514936:CXCR4 protein, mouse; D039041:Integrin alpha4beta1; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1