B-cell homeostasis requires complementary CD22 and BLyS/BR3 survival signals.
Peripheral B-cell numbers are tightly regulated by homeostatic mechanisms that influence the transitional and mature B-cell compartments and dictate the size and clonotypic diversity of the B-cell repertoire. B-lymphocyte stimulator (BLyS, a trademark of Human Genome Sciences, Inc.) plays a key role in regulating peripheral B-cell homeostasis. CD22 also promotes peripheral B-cell survival through ligand-dependent mechanisms. The B-cell subsets affected by the absence of BLyS and CD22 signals overlap, suggesting that BLyS- and CD22-mediated survival are intertwined. To examine this, the effects of BLyS insufficiency following neutralizing BLyS mAb treatment in mice also treated with CD22 ligand-blocking mAb were examined. Combined targeting of the BLyS and CD22 survival pathways led to significantly greater clearance of recirculating bone marrow, blood, marginal zone and follicular B cells than either treatment alone. Likewise, BLyS blockade further reduced bone marrow, blood and spleen B-cell numbers in CD22(-/-) mice. Notably, BLyS receptor expression and downstream signaling were normal in CD22(-/-) B cells, suggesting that CD22 does not directly alter BLyS responsiveness. CD22 survival signals were likewise intact in the absence of BLyS, as CD22 mAb treatment depleted blood B cells from mice with impaired BLyS receptor 3 (BR3) signaling. Finally, enforced BclxL expression, which rescues BR3 impairment, did not affect B-cell depletion following CD22 mAb treatment. Thus, the current studies support a model whereby CD22 and BLyS promote the survival of overlapping B-cell subsets but contribute to their maintenance through independent and complementary signaling pathways.
Department of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710, USA.
Susan H
SH
Smith
Karen M
KM
Haas
Jonathan C
JC
Poe
Koichi
K
Yanaba
Christopher D
CD
Ward
Thi-Sau
TS
Migone
Thomas F
TF
Tedder
D000818:Animals; D053264:B-Cell Activating Factor / Q000276:immunology*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D051918:Sialic Acid Binding Ig-like Lectin 2