During the humoral response to an antigen, B cells differentiate into memory cells and antibody-secreting plasma cells. The response is triggered by the recognition of the antigen by the B-cell receptor (BCR). The BCR is an oligomer consisting of antigen-specific, membrane-bound immunoglobulin and a signal transduction heterodimer, Ig-α/Ig-β (CD79). Cross-linking of the BCR by a multivalent Ag is the classical model of the activation of immunogenic signaling pathways.1 Antigen is presented to the BCR by follicular dendritic cells, dendritic cells, and macrophages. Subsequently, antigen is internalized into endosomal compartments containing major histocompatibility complex (MHC) class II molecules and undergoes proteolytic processing. Antigenic peptides bound to MHC class II are transported to the cell surface. As a consequence, B cells become antigen-presenting cells for helper T cells, which leads to further B-cell activation, affinity maturation of antibody, and immunoglobulin class switching.
Thaunat et al., in the laboratory of Facundo Batista at the London Research Institute, used sophisticated cellular imaging methods to follow the fate of internalized antigens in a murine model system. This system included fluorescently labeled transgenic B cells, designated MD4 cells, expressing BCRs specific for hen egg lysozyme (HEL), and HEL-conjugated beads (bHEL) to simulate a multivalent antigen on a microorganism. Following adoptive transfer of MD4 cells into normal (C57BL/6) mice and immunization of the mice with bHEL, the antigenconjugated beads were shown to be localized in B-cell uropods (the protrusion at the rear of polarized motile cells). Additionally, MD4 cells cultured in vitro with bHEL and stimulated with both IL-4 and CD40 displayed polarized localization of bHEL. Importantly, B cells maintained a polarized distribution of antigen after cell division. The authors tested two possible models of antigen distribution on cell division. According to the first model, each daughter cell would receive an equal amount of internalized antigen. In this model, several cell divisions would be required for antigen to be diluted to undetectable levels in progeny cells. In the second model, one daughter cell would receive the entire antigen load. This model predicts the presence of daughter cells lacking antigen after only one cell division. Flow cytometric analysis performed on both in vitro and in vivo samples provided experimental support for the second model.
Antigen Internalized by B Cells is Transported to the MHC Class II Compartment (red). Only one daughter B cell receives antigen during asymmetric inheritance of this compartment.
Antigen Internalized by B Cells is Transported to the MHC Class II Compartment (red). Only one daughter B cell receives antigen during asymmetric inheritance of this compartment.
The authors examined the functional significance of the differential distribution of antigen during cell division. They sorted B cells into populations containing either high or low levels of bHEL and measured HEL peptide bound to MHC on the cell surface. HEL-MHC concentrations were higher for B cells that contained high levels of bHEL, indicating that they are more efficient at antigen presentation. Additionally, using bHEL-ovalbumin (bHEL-OVA) conjugate as the antigen and HEL-specific B cells as antigen-presenting cells, they observed that IL-2 secretion and proliferation of co-cultured OVAspecific T cells was greater in the presence of B cells containing higher amounts of bHEL-OVA.
In Brief
This study raises the question of why it would be advantageous for the immune system to distribute antigen asymmetrically during B-cell expansion. The authors speculate that antigen-loaded daughter B cells may compete more effectively for limiting amounts of T-cell help. Additionally, antigen-poor daughter cells are poised to mutate their BCR and will survive only if high-affinity surface immunoglobulin is generated. And in a Perspectives commentary accompanying the article, Dustin and Meyer-Hermann describe a mathematical model that predicts that asymmetric inheritance of antigen can lead to more efficient production of plasma cells.2
The study by Thaunat et al. produced the surprising observation that there is an asymmetric distribution of internalized antigen in polarized B cells that persists after cell division. This property may play an important regulatory role in the production of high-affinity antibodies, immunoglobulin class switching, and the generation of antibody-secreting plasma cells.
