If B cells are the immune system’s munitions factories, making antibodies to neutralize harmful pathogens, then the tiny biological structures known as germinal centers are its weapons development facilities. Formed in response to infection and vaccination, these microscopic training grounds allow B cells to hone the antibodies they deploy once morest specific viruses and bacteria.
Understanding the functioning of germinal centers is therefore crucial for understanding immunity and developing more effective vaccines. Now a new study in Cells reveals why some germinal centers persist for months rather than weeks, providing information that might inform future vaccine design.
Old bottle, new wine
Germinal centers form in the lymphatic tissues of the body soon following vaccination or infection. Once inside a germinal center, B cells undergo rapid mutations and, through a process of natural selection, only B cells with antibodies that bind most efficiently to their target antigens survive. These higher B cells then become either plasma cells, antibody factories that secrete large amounts of antibodies into the serum, or memory B cells, which patrol the body looking for signs of the agent returning. pathogen they have evolved to fight.
The goal of the germinal center is to generate high affinity plasma cells and memory B cells, which it then exports. »
Renan VH de Carvalho, postdoctoral fellow in the laboratory of Gabriel D. Victora at Rockefeller University
In mice, most germinal centers close following a few weeks, having achieved their goal of producing high-affinity B cells. But those that form in response to certain respiratory infections, including the flu, can remain active for more than six months, regarding a quarter of a mouse’s normal lifespan. De Carvalho and his colleagues wanted to understand why these germinal centers are so long-lived and what precisely is going on there.
For the study, the researchers first infected mice with influenza and SARS-CoV-2 viruses, waited for them to form germinal centers, and then sequenced the antibody genes from the harvested B cells. in these centers over 24 weeks. To their surprise, they found that, rather than continually progressing at a steady rate, antibody optimization peaked following 12 weeks and then apparently regressed even as the center remained active. This puzzling drop was due to the continued introduction of non-evolved “naive” B cells into the germinal centers, the researchers later found.
As the weeks turned into months, a more complete picture began to form: the founder B cells that had originally seeded the long-lived germinal centers were gradually replaced by naïve cells, so that only a a tiny fraction of the late germinal centers were made up of the progeny of the B cells that started them.
Old school vs new school
These new recruits did not behave like the original B cells in the germinal center. Later experiments showed that while naïve B cells also evolved inside germinal centers, they did not produce antibodies that might bind to influenza or SARS-CoV2 antigens.
“We used to think of infection-induced germinal centers as a single reaction targeting antigens of a particular pathogen,” de Carvalho explains. “Apparently not, at least in the case of these long-lived germinal centers. »
But the few original B cells that remained were enough to produce effective immunity once morest the initial pathogen. When the researchers re-exposed the mice to influenza antigens 3 months following their first infection; effectively mimicking repeated infection or a booster injection; they demonstrated that many memory B cells that started pumping out antibodies descended from the few founder cells that persisted in germinal centers for many months, not their naive replacements.
“Even if they make up a small fraction of the total cell number later, the founder cells that stay in the germinal center for a long time continue to do their job,” de Carvalho explains. But how well these founding B-cells do their job, and whether naïve recruits restrict their style and reduce their effectiveness, remains to be seen. Future studies from the Victora lab will address this question.
Meanwhile, the findings already have implications for our general understanding of how germinal centers work. Understanding the dynamics between founder and naïve B cells might help researchers take advantage of long-lived germinal centers to produce more effective antibodies once morest dangerous respiratory viruses, such as influenza and SARS-CoV-2.
“The invasion of ongoing germinal center structures by sequential waves of B cells may prove to be an important factor in predicting germinal center outcomes, perhaps far beyond this particular model of influenza,” says Victora, “and might give us some insight into how to coax germinal centers to produce the antibodies we need. »
