Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling


The survival of transitional and mature B cells requires both the B cell antigen receptor (BCR) and BLyS receptor 3 (BR3), which suggests that these receptors send signals that are nonredundant or that engage in crosstalk with each other. Here we show that BCR signaling induced production of the nonclassical transcription factor NF-κB pathway substrate p100, which is required for transmission of BR3 signals and thus B cell survival. The capacity for sustained p100 production emerged during transitional B cell differentiation, the stage at which BCR signals begin to mediate survival rather than negative selection. Our findings identify a molecular mechanism for the reliance of primary B cells on continuous BR3 and BCR signaling, as well as for the gradual resistance to negative selection that is acquired during B cell maturation.

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Figure 1: BLyS expression on splenic and bone marrow B cells.
Figure 2: Continuous BLyS signaling is required for p100 processing and sustained nuclear accumulation of p52.
Figure 3: NF-κB crosstalk 'downstream' of BCR and BR3 signaling in follicular B cells.
Figure 4: BCR signaling blockade decreases tonic and anti-IgM–stimulated p100 generation.
Figure 5: BCR signaling blockade decreases BLyS-mediated signaling and long-term survival.
Figure 6: Effect of blocking tonic BCR signals on nonclassical NF-κB components.
Figure 7: T1 B cells have a diminished capacity to upregulate p100 after BCR stimulation in vitro.

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We thank M. May, L. Solt and the University of Pennsylvania Flow Cytometry Core for assistance and advice; C.A. Hunter (University of Pennsylvania School of Veterinary Medicine) for NF-κB p50–deficient mice; C. Thompson (University of Pennsylvania) for mice with B cell–specific expression of the Bcl-xL transgene; V. Dixit (Genentech) for pRK5B-hBR3; and J.M. Stadanlick for critical reading of this manuscript. Supported by the US Public Health Service (R01AI073939 and R01AI0545488 to M.P.C.; T32HL07971 to J.E.S.; T32AI055428 to F.G.K.; and R01AI032592 to J.G.M.) and the Intramural Research Program of the National Institute on Aging.

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J.E.S., M.K., F.G.K., J.L.S., J.P.M., W.J.Q., R.J.B., L.S.T. and K.A.J. did research, analyzed data and generated key reagents; J.E.S., M.K., J.G.M., R.S. and M.P.C. designed research and analyzed data; and J.E.S., R.S., M.K. and M.P.C. wrote the paper.

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Correspondence to Michael P Cancro.

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Stadanlick, J., Kaileh, M., Karnell, F. et al. Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling. Nat Immunol 9, 1379–1387 (2008).

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