Research findings solve the paradox of how the immune system balances speed and precision

Germinal centers are high-speed evolution machines. Tiny clusters in the lymph nodes, germinal centers refine antibodies through mutation and expansion until they produce high-affinity B cells adapted to keep different pathogens in check. But rapid evolution should come at a cost. Most mutations are deleterious, so constant mutation during every cell division, coupled with unchecked proliferation, should be a recipe for disaster. How B cells somehow rapidly mutate and improve all at once was a long-standing mystery. 

Now, advanced imaging techniques reveal the germinal center's secret weapon: the ability to suppress mutation during rapid proliferation. This built-in safeguard allows germinal centers to mass-produce successful clones without compromising antibody quality. The findings, published in Nature, solve the paradox of how the immune system balances speed and precision. 

The germinal center is using a really smart strategy to do two things at once-two things that are, at face value, incompatible."

Gabriel D. Victora, Head of the Laboratory of Lymphocyte Dynamics

Mutate-and-check 

Since the early 1990s, scientists have known that B cell evolution is unusual. Mathematical modeling from that era suggested that germinal centers improve antibodies by alternating between mutation and selection-mutations occur once every division cycle, followed by a testing phase, in which B cells with harmful mutations die out and those with the strongest antibodies multiply on. This mutate-and-check scheme shaped our understanding of B cell evolution for decades. 

"This particular model was one of the most important contributions of mathematical modeling to immunology," Victora says. 

But in 2016, the Victora lab discovered clonal bursting, a phenomenon in which a single B cell multiplies so rapidly that it takes over the entire germinal center. This kind of unchecked proliferation didn't fit with the cautious step-by-step process proposed in the 1990s. Then, in 2021, the lab showed that clonal burst happen by what they dubbed "inertial" cell cycling, in which B cells multiply continuously without selection between each round. Neither finding fit with the mutate-and-check model. "At some point we realized there must be a rule that prevents mutation during inertial cycles," Victora says.

Pause-and-proliferate 

To find this elusive rule, the team used a number of advanced imaging techniques. With Brainbow imaging-a genetic cell-labeling technique-they were able to spot clonal bursts: single B cells dividing so rapidly that they took over the entire germinal center. Surprisingly, the population of cells that resulted from these bursts had fewer mutations than expected, suggesting that B cells are placing mutation "on hold" while they carry out inertial proliferation. 

Then, in mice engineered with a fluorescent reporter protein, they pinpointed the precise moment in the cell cycle in which B cells mutate. What they found was striking-during inertial cycling, bursting B cells skip precisely the cell cycle phase in which mutation takes place. To confirm this finding, they used image-based cell sorting, isolating B cells and sequencing them to demonstrate that only B cells in the paused state were accumulating mutations, demonstrating that mutation is restricted to this stage-and that skipping it is how some B cells avoid mutating during inertial cycles. Combining these findings with mathematical models confirmed that germinal centers dynamically regulate mutation, turning it on and off to generate the highest affinity B cells without sacrificing speed. 

"Imaging was key in making this project work," says Juhee Pae, a research associate in the Victora lab, who was also the lead author on the 2021 paper. "Together, these techniques pointed us to the issue, allowed us to figure out the particular stage of the cell cycle being skipped, and then helped us isolate cells to see which were making the mutation." 

The results reveal how germinal centers refine antibody responses with maximum efficiency. By demonstrating that B cells suppress mutation during rapid proliferation and resume it only after expansion, the findings explain how the immune system quickly makes many copies of the best B cells while still improving their ability to fight infections. These principles, which shed light on precise mechanisms shaping adaptive immunity, may have broader implications for vaccine design and immune therapies. 

"There's a mini-evolution machine inside our lymph nodes-and I like to think about the study of germinal centers as trying to figure out how a clump of cells forms such an efficient machine," Victora says. 

"It's such fundamental knowledge," Pae adds. "We're learning how our immune system works."