Abstract
SummaryFollicular B cell survival requires signaling from BAFFR, a receptor for BAFF and the B cell antigen receptor (BCR). This “tonic” BCR survival signal is distinct from that induced by antigen binding and may be ligand-independent. We show that inducible inactivation of the Syk tyrosine kinase, a key signal transducer from the BCR following antigen binding, resulted in the death of most follicular B cells because Syk-deficient cells were unable to survive in response to BAFF. Genetic rescue studies demonstrated that Syk transduces BAFFR survival signals via ERK and PI3 kinase. Surprisingly, BAFFR signaling directly induced phosphorylation of both Syk and the BCR-associated Igα signaling subunit, and this Syk phosphorylation required the BCR. We conclude that the BCR and Igα may be required for B cell survival because they function as adaptor proteins in a BAFFR signaling pathway leading to activation of Syk, demonstrating previously unrecognized crosstalk between the two receptors.
Highlights
B lymphocytes play a critical role in the adaptive immune response, in part by producing high affinity antibodies to pathogens
We found that 3 weeks after the start of tamoxifen treatment pre-B and immature B cells were lost from the bone marrow, all transitional and marginal zone B cells and around 80% of follicular B cells were lost from the spleen, whereas most B1 cells persisted in the peritoneum (Figures S1F–S1I)
We found that the amount of phosphorylated Akt was reduced in Syk-deficient B cells both before and after stimulation with BAFF (Figure 5A), consistent with Syk transducing both the B cell antigen receptor (BCR) survival signal and a BAFFR signal leading to activation of PI3 kinase
Summary
B lymphocytes play a critical role in the adaptive immune response, in part by producing high affinity antibodies to pathogens. The total number of mature naive (unactivated) B cells remains largely constant despite continuous production of new B cells in the bone marrow as well as recruitment of naive B cells into antigen-activated compartments, such as germinal center cells, plasma cells, and memory B cells. This homeostasis of mature B lymphocytes is known to depend on at least two receptors: BAFFR (TNFRSF13C) and the B cell antigen receptor (BCR). This promotes the proteolytic processing of NF-kB2 (p100) into p52, an NF-kB family transcription factor that translocates into the nucleus and regulates gene expression (Rickert et al, 2011)
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