Phone calls within a cell
The team led by Dr. Palash C. Maity and Prof. Dr. Michael Reth found that these receptors are not only co-localized at nanometer distance but also functionally connected (Becker et. al., 2017). Their work addresses the long-standing question about the function of IgD on the mature B cell surface.
B-lymphocytes (B cells) are an important part of our adaptive immune system. They are capable of detecting invading pathogens via their B Cell Antigen Receptor (BCR). B cells carry two different classes of BCRs on their surface, called IgM and IgD. Why these two flavors of BCR exist is still a conundrum. B cells are highly mobile cells that patrol throughout the body and can migrate into areas of infection. For their directed migration B cells have additional receptors on their surface, called chemokine receptors, which enable them to follow certain environmental cues. One of the most prominent chemokine receptors is called CXCR4 that also plays a central role in HIV infection and many cancers.
The research team around Dr. Palash Maity has now revealed a novel connection between the IgD-BCR and CXCR4. “Traditionally, surface receptors are thought of working separated from each other. One particular receptor is activated through binding of its specific ligand, that’s it”, Dr. Maity explains. He further adds: “We have now found that this is not the complete story. First, receptors are not sitting around alone on the cell surface, but are densely packed with other receptors in their proximity. This packaging of receptors is highly specific.” The team had previously shown that cell surface receptors are organized in so called protein islands on the cell surface (Maity et. al., 2015). They have now shown that the co-localization of receptors in protein islands also has functional implications. The current study shows that the IgD-BCR and the CXCR4 chemokine receptor are close neighbors on the B cell surface and that the IgD-BCR is required for CXCR4 to function. In other words, a second receptor, which is not even seeing its ligand, is required for the first receptor to function. “This means that these two receptors have to communicate or cross-talk in some way”, Dr. Martin Becker, the first author of the current study says. “We have found that this cross-talk is mediated through the cytoskeleton of the cell, which is located just beneath the surface. You can imagine this like two households who talk to each other on the phone where the connection is established through a glass fiber cable in the ground”, Dr. Becker explains further. To stay with the telephone picture, in order to establish a connection a service provider is generally required as the lynchpin. The same is true for the B cell, which uses the co-receptor CD19 to establish the connection between CXCR4 and the IgD-BCR. The authors found during their work that CD19 is required to integrate the signals initiated through ligand binding to CXCR4. But for CD19 to perform its job properly, the IgD-BCR (and not the IgM-BCR) is essential. As with the phone call, the service provider (CD19) needs to connect two houses (CXCR4 and the IgD-BCR), in order to establish a function (the phone call).
These findings, that highlight the central role for the cytoskeleton in the communication between receptors, are not only important for basic research but also for applied clinical science. Indeed, CXCR4 and the BCR are central players in the establishment of lymphomas. The newly discovered cross-talk between these two receptors and CD19 could provide new insight in the growth control of these cancers and how to tackle them therapeutically.
CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor.
Becker M, Hobeika E, Jumaa H, Reth M, Maity PC.
Proc Natl Acad Sci U S A. 2017 May 1. [Epub ahead of print]