Survival artists
B cells can survive without B cell receptor
Scientists at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and at the Institute of Immunology in Ulm investigate the molecular and structural mechanisms required for the survival of B cells. Previous studies indicated that B cells without a functioning B cell antigen receptor (BCR) die rapidly. Researchers led by Dr. Elias Hobeika and Prof. 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 Elias Hobeika and Michael Reth from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the Universities of Freiburg and Ulm 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.
Figure 1: B cell receptor (BCR) on the surface of the B cell with heavy chains (HC), light chains (LC) and the signal unit with the proteins Igα and Igβ.
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 signaling unit consisting of the proteins Igα and Igβ (Fig. 1). This signaling 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 Elias 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” (Fig. 2).
Figure 2: Schematic representation (upper panels) and FACS analysis (lower panels) of B cells derived from a mutant mouse strain, which allows for the inactivation of Igα. Before tamoxifen treatment (left), the cells express a BCR and the BAFF-R. After tamoxifen treatment (right), the cells lose Igα and subsequently BCR expression, however retain BAFF-R expression and function.
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 signaling pathways. „Our in vivo experiments provide strong evidence that BAFF-R signaling is crucial for the survival of Igα-deficient B cells, independent 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 signaling 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.
