Cells scrambling for a spot in a germinal center face an intense acceptance process. Germinal centers are formed after exposure to a pathogen or vaccine, and act as a kind of training academy for the immune system, helping B cells improve their response to a threat. Only B cells with a higher affinity for the pathogen or vaccine get into these structures, where they undergo waves of mutations to produce successively stronger antibodies.
But one curious thing about this process has long puzzled scientists: Germinal centers seem to change acceptance criteria over time. In later stages of germinal center existence, B cells with little or no affinity for virus populate the once exclusive site, eventually making up to 30 percent of its graduates. Now, a new study in Cell describes this phenomenon in detail and suggests that high-affinity B cells — the same cells that marginalize lower B cells in the early stages — trigger this late-stage shift of germinal centers. The findings shed new light on how the immune system mounts its response to infections like COVID and HIV.
Germinal centers are open structures that receive B cells continuously. Over time, the threshold for adherence is lowered, and this leads to a more diverse pool of effector cells.”
Michelle C. Nussensweg, Zanvil A.Cohn and Ralph M. Steinman Professor at The Rockefeller University
within the germinal center
For the study, Nussensweg and colleagues tracked B cells in the germinal centers of mice. They first showed that in early germinal centers, B cells enter based on their ability to bind to a vaccine antigen. Because there is a limited supply of antigen in the region, high-affinity B cells (those with receptors that are particularly adept at binding antigen) pick up antigen and are duly inserted into the germinal center. The less affinity B cells are left fumbling outside.
How, then, do these low-affinity antibodies gain entry into the late germinal center phase? Upon further investigation, the team found that in the late germinal-center stage, elite B cells begin to produce antibodies that bind to antigen-presenting dendritic cells. A dense forest of antigen-antibody complexes begins to block the area, and the equivalent of a molecular traffic jam ensues. The result is that a previously scarce antigen is suddenly ready to be taken up. Low-affinity B cells bind any antigen that is around them, and this is their ticket to the germinal center.
Ironically, this means that the same high-affinity B cells that carry low-affinity B cells out of the early-stage germinal center eventually trigger the same process by which those lower-affinity cells are eventually accepted. “Our paper doesn’t just identify and document this phenomenon,” says Nussensweg. “It shows that the mechanism by which this occurs is antibody dependent.”
In theory, introducing naïve B cells into the germinal center accomplishes one of the larger goals of the immune system. “Variety is a key feature of immunity,” says Nussensweg. “The immune system as a whole does many things to maximize diversity, and here the germinal centers strive for a diverse immune response by lowering the threshold and allowing more cells to join.”
Naïve B cells, which have less time to mutate when they invade the germinal center in the late stage, will inevitably emerge different from those elite B cells that have been around all along. Whether this kind of diversity in the range of immune cells that encounter a pathogen helps or hinders depends on the virus in question. “It can be a very positive thing or a very negative thing,” says Nussenweg.
Take SARS-CoV-2, a virus with multiple antigen fragments (known as epitopes) that antibodies can use to identify and latch on to the virus. After leaving the germinal center, naïve B cells produce antibodies different from mature ones, which will cleave to different epitopes; Each attacks the virus from its own angle. If the virus mutates to make one antibody less effective or becomes obsolete, others can provide cover. “Variety gives you more targets, and you can make antibodies to other parts of the molecule,” says Nussenweg. “For SARS viruses, it’s great, and it’s partly responsible for our ability to fight off variants when we get infected.”
Not so with HIV, a virus with precious few epitopes. As described by Nussenzweig and colleagues in a recent study, the body stops producing an entire batch of antibodies if it detects an excess of antibodies with minimal potency. Here, a diverse response increases the possibility that low-affinity antibodies will bind to one of the only HIV epitopes poorly, which can cause the body to take a large part of the immune response offline. Similar antibodies that would have worked better may never be allowed to form. “For HIV, it gets in the way of an effective vaccine,” says Nussensweg.
The team hopes that their findings will inform future attempts to develop a vaccine, while rounding immunologists’ understanding of how the body responds to disease.
Hagloff, T., et al. (2022) Continuous invasion of the germinal center contributes to the diversity of the immune response. cell. doi.org/10.1016/j.cell.2022.11.032.