MRC National Institute for Medical Research, London

Science for Health

Main navigation

Home
News

News & events

News
- Archive

Receptor cross-talk controls B cell survival

28 February 2013

Researchers at NIMR have shown that B cell survival depends on unexpected cross-talk between a receptor for the BAFF cytokine and the B cell antigen receptor. The work is published in Immunity.

B cells are white blood cells that play a key role in the immune response, in part by producing antibodies in response to infectious pathogens. The number of B cells in the adult mammal remains constant despite continuous input of new B cells that are being generated in the bone marrow and continuous output of cells from this pool to become antibody-secreting cells. The size of this pool is maintained by carefully regulated survival signals.

We know of two protein receptors on the surface of B cells that control their survival. BAFFR is a receptor for the cytokine BAFF. Binding of BAFF to the extracellular domain of BAFFR sends a signal into the B cell that is critical for its survival. B cells also need the B cell antigen receptor (BCR) to survive. The BCR is surface-bound antibody, and the main function of this receptor is thought to be to bind antigen, for example from infectious pathogens. Binding of antigen causes the BCR to deliver a signal to the B cell that results in activation of the B cell, and its subsequent proliferation and differentiation into antibody-secreting cells. About 15 years ago, a surprising discovery made by the group of Klaus Rajewsky (then at the University of Cologne) showed that in addition to its function in responding to antigen, the BCR was also required for survival of B cells, leading to the proposal that independent of binding antigen the BCR delivers a continuous low-level ”tonic” signal that is required for B cell survival.

In the current work, Edina Schweighoffer, working in the group of Victor Tybulewicz (pictured) in NIMR’s Division of Immune Cell Biology, in collaboration with scientists at GSK and the University of Dundee, showed, unexpectedly, that the two receptors, BAFFR and BCR, work closely together to ensure B cell survival. In particular they showed that binding of BAFF to BAFFR sends a signal into the B cell that results in phosphorylation of key tyrosines found in intracellular domains of the BCR. These phosphorylated tyrosines then bind to the Syk tyrosine kinase, resulting in activation of its enzymatic activity. Furthermore, the Syk kinase was critical for B cell survival and identified two pathways downstream of Syk that contribute to this function.

This work changes our understanding of how these key receptors function. We had previously thought that BAFFR and BCR each deliver a separate survival signal to the B cell. However Edina’s work shows that BAFFR has co-opted the signaling machinery of the BCR to transduce survival signals. So, rather than providing a stand-alone tonic survival signal, it appears that the BCR is acting as an adapter protein, relaying key BAFFR survival signals.

Victor Tybulewicz

Binding of BAFF to BAFFR results in phosphorylation of tyrosines in the ITAM motifs of the BCR, which in turn bind Syk, activating its kinase activity. Syk transduces signals through the ERK kinase and PI3 kinase (PI3K) pathways required for survival of B cells. Independently of this, BAFFR also transduces survival signals through IKK1 and NFκB2.