Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers.
Striking cell losses occur during late B lymphocyte maturation, reflecting BcR-mediated selection coupled with requisites for viability promoting signals. How selection and survival cues are integrated remains unclear, but a key role for B lymphocyte stimulator (BLyS(TM); trademark of Human Genome Sciences, Inc.) is suggested by its marked effects on B cell numbers and autoantibody formation as well as the B lineage-specific expression of BLyS receptors. Our analyses of the B cell-deficient A/WySnJ mouse have established Bcmd as a gene controlling follicular B cell life span, and recent reports show Bcmd encodes a novel BLyS receptor. Here we show that A/WySnJ B cells are unresponsive to BLyS, affording interrogation of how Bcmd influences B cell homeostasis. Mixed marrow chimeras indicate A/WySnJ peripheral B cells compete poorly for peripheral survival. Moreover, in vivo BrdU labeling shows that (A/WySnJ x BALB/c)F(1) B cells have an intermediate but uniform life span, indicating viability requires continuous signaling via this pathway. Together, these findings establish the BLyS/Bcmd pathway as a dominant mediator of B cell survival, suggesting competition for BLyS/Bcmd signals regulates follicular B cell numbers.
Harless
S M
SM
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lentz
V M
VM
Sah
A P
AP
Hsu
B L
BL
Clise-Dwyer
K
K
Hilbert
D M
DM
Hayes
C E
CE
Cancro
M P
MP
D000818:Animals; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000166:cytology*; D002470:Cell Survival / Q000502:physiology; D006579:Heterozygote; D018655:Lymphocyte Count; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D053265:B-Cell Activation Factor Receptor; C120197:BLyS receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C486662:Tnfrsf13c protein, mouse