A new study in Cell has revealed that the cutthroat admissions process in germinal centers, which act as a kind of immune system “training academy”, changes over time. Germinal centers form after exposure to a pathogen or vaccine and help B cells refine their response to the threat. B cells with the highest affinity for the pathogen or vaccine gain entry to these structures, where they undergo waves of mutations to produce successively stronger antibodies.
However, in the later stages of a germinal center’s existence, B cells with little or no affinity for the virus flood the once-exclusive site — a paradox that has long stumped researchers.
The study, led by Rockefeller professor Michel C. Nussenzweig, aimed to understand this phenomenon in more detail and suggests that high-affinity B cells, the same ones that sideline inferior B cells in the early stage, trigger this change in late-stage germinal centers.
The team tracked B cells in germinal centers in mice and found that in early-stage germinal centers, B cells enter based on their ability to bind to a vaccine antigen. High-affinity B cells nab an antigen and are admitted into the germinal center, while low-affinity B cells are left outside.
However, upon further investigation, the team found that in the late-stage germinal center, elite B cells start producing antibodies that bind to dendritic cells presenting antigens. This creates a dense forest of antigen-antibody complexes, clogging the area and causing a molecular traffic jam. The result is that formerly scarce antigen is suddenly available for low-affinity B cells to bind, allowing them to enter the germinal center.
This paradoxical process means that the same high-affinity B cells that shoulder low-affinity B cells out of the germinal center in the early stages set in motion the process by which those inferior cells are ultimately admitted. The team found that this mechanism is antibody-dependent.
In theory, introducing naive B cells into the germinal center accomplishes one of the larger goals of the immune system, which is to maximize diversity. Naive B cells, which have less time to mutate when they invade the late-stage germinal center, will inevitably come out different than those elite B cells that were there all along.
The diversity in the range of immune cells that encounter the pathogen can have positive or negative effects depending on the virus. For example, after SARS-CoV-2, a virus with multiple bits of antigen (known as epitopes) that antibodies use for virus identification and attachment, leaves the germinal center, naive B cells produce different antibodies than mature ones, which will attach to other epitopes and attack the virus from different angles.