B cells as survival artists
Previous studies indicated that B cells without a functioning B cell antigen receptor (BCR) die rapidly. Researchers led by Dr. Elias Hobeika from the University of Ulm and BIOSS speaker Prof. Dr. Michael Reth now show that under specific circumstances some B cells can survive despite the loss of BCR on their surface.
B lymphocytes are an important part of our adaptive immune system. B cells detect antigens with their B cell antigen receptor (BCR), which lies on their surface. Upon the binding of an antigen to the BCR, B cells are activated and differentiate into antibody-producing plasma cells to support the immune response.
The team led by Hobeika and Reth studies the structural organization and regulation of BCRs. Based on previous studies it was assumed that BCRs are not only essential for the function of the B cells, but also indispensable for the survival and the maintenance of mature B cells. However, the researchers from Freiburg were now able to demonstrate that under certain circumstances B cells are capable to survive without a BCR.
In collaboration with Klaus Rajewsky from the Max Delbrück Center for Molecular Medicine in Berlin, the scientists made use of a mouse strain that allows manipulation of the BCR in already matured B cells. The BCR located on the cell surface comprises two identical protein heavy chains (HC), two identical protein light chains (LC) and a signalling unit consisting of the proteins Igα and Igβ. This signalling unit is responsible for the transmission of extracellular signals into the cell.
In their experiments, the scientists deleted either the HC or the protein Igα of the BCR. In both cases, the receptor disappeared from the cell surface and the B cells lost their ability to detect antigens. “When we checked the survival of these two sets of B cells, we were quite surprised,” says Hobeika. “B cells lacking the heavy chains died as expected, whereas B cells deficient for Igα continued to live. “A closer look at the Igα-deficient cells revealed that, unlike the HC-deficient cells, they retained the Igβ protein on their cell surface.”
Furthermore, the scientists demonstrated that Igα-deficient B cells depend on the function of another receptor for their survival. This receptor binds the B cell-activating factor BAFF and is known to have an integral function in ensuring the maintenance of mature B cells and promoting cell survival using prominent pro-survival signalling pathways. „Our in vivo experiments provide strong evidence that BAFF-R signalling is crucial for the survival of Igα-deficient B cells, independently of the BCR“, says the first author of the study, Ella Levit-Zerdoun.
These new findings might also provide additional insights about into the role of B cell receptors in cancer. In some B cell tumors, absence of the Igα signalling unit has been associated with a poor prognosis. Understanding the survival mechanisms of Igα-deficient B cells could therefore identify novel avenues to interfere with the maintenance of these malignant B cells.
Michael Reth is the scientific director of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies. He is also a professor at the Institute of Biology III at the University of Freiburg and head of a research group at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg. Elias Hobeika is group leader at the Institute of Immunobiology at the University of Ulm.
Original publication:
Survival of Igα-Deficient Mature B Cells Requires BAFF-R Function.
Levit-Zerdoun E, Becker M, Pohlmeyer R, Wilhelm I, Maity PC, Rajewsky K, Reth M, Hobeika E.
J Immunol. 2016 Mar 1;196(5):2348-60
http://www.jimmunol.org/content/196/5/2348.long