Publication Q&A: B Cell Adapter Protein Coordinates Antigen Internalization and Trafficking Through the B Cell Receptor

March 21, 2025 – Mridu Acharya, PhD, an immunology researcher in Seattle Children’s Research Institute’s Center for Immunity and Immunotherapies, together with colleagues, identified a new mechanism by which immune cells internalize products from pathogens and position these pathogen products inside the cells to signal an appropriate antibody response.

The study shows the location of the internalized pathogen product inside the immune cell is key to determining the outcome of immune response. The team identified a protein expressed on B cells, BCAP, is required for internalization of pathogen products and their positioning in the central areas of the B cells. This allows the B cell to make antibodies against this product. This BCAP-dependent internalization process is also important for the B cells to present parts of these pathogenic products to another immune cell type, T cells, so the T cells can also mount a response against these pathogens.

Using lab models that lack the BCAP protein only on B cells and cutting-edge microscopy techniques, the researchers found a loss of the protein BCAP from B cells, leads to inefficient internalization of the pathogen products — the internalized product was stuck in the peripheral areas of the cell and unable to move into central compartments inside the cells. As a result, the small-animal models that have B cells without the BCAP protein cannot make antibodies against pathogens and also cannot activate T cells to respond to the pathogens.

Children’s contributing authors: Mridu Acharya, PhD (senior author), Jonathan Lagos, MD, PhD (first author), Ursula Holder, PhD, Sara Sagadiev, PhD, and Andrea Montiel-Armendariz.

Read this article in the journal Science Advances (published Nov. 15, 2024).

What does this immune cell research tell us that we didn’t know before?

It was known previously that encounters with products from pathogens and their internalization is an important step to induce immune response to pathogens. However, key proteins involved in pathogen product internalization were not known and the study shows that BCAP is an important protein involved in initiating pathogen product internalization. Additionally, the study shows that BCAP is involved in determining the location or positioning of the internalized product inside the cell and this positioning determines the type of B cell activation.

The data show that inefficient internalization and peripheral positioning of the pathogen product leads to certain features of B cell activation, such as switching of antibody isotypes, while efficient internalization leads to positioning of the pathogen product in the central compartments of the cell, which is important to ensure adequate pathogen-specific antibody production, as well as T cell activation. These details about positioning of pathogen products could allow us to manipulate different features of immune response by manipulating the positioning of pathogenic products inside the cell.  

What are the broad implications of this B cell and T cell research?

First, this research allows us to understand the basic biology of B cells. It reveals how B cells internalize products from bacteria or viruses or from our own cells. It also reveals key players involved in this internalization process and how the internalization process determines the final outcome of antibody response, as well as T cell activation. This information can be used to design more effective vaccines that lead to better antibody response against vaccine products. This research could also help us in further investigate what happens during autoimmune diseases when B cells start processing products from our own cells and initiate immune response against components of our own bodies.

What are the next steps and long-term goals for this immunology research?

We have used novel microscopy techniques to study positioning of pathogen products inside the B cells for this study. We are now using this technology to further understand how B cells process products from different types of pathogens and investigate features of compartments inside B cells where pathogenic products reside. The goal is to find new proteins found in these compartments that could be manipulated to increase or decrease antibody response to pathogen or vaccine products.

We are performing such studies now with both preclinical models and human B cells to ensure we can translate our findings from lab models into human systems. Moreover, we are also using our findings to study why some self-reactive B cells also make antibody responses to products from our own cells. We are investigating how products from our own cells are internalized and positioned inside the cell in the case of autoimmune diseases. This could allow us to devise strategies to prevent autoimmune diseases.