How the immune system gets better at detecting pathogens
· Medical Xpressby Kristel Tjandra, Yale University
edited by Sadie Harley, reviewed by Andrew Zinin
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B cells, a type of white blood cell, protect our bodies by producing antibodies that recognize and bind to invaders like bacteria and viruses. After an infection, B cells undergo rapid mutations in the genes that encode antibodies. These mutations—known as somatic hypermutations—allow B cells to produce antibodies tailor-made to recognize the foreign pathogens they just encountered, making them more efficient at defense.
This is a key part of our immune system and how it adapts to new pathogens. But how cells unleash such an extreme kind of mutation—occurring at a rate 1 million times higher than in other genetic regions—in a defined stretch of DNA has remained unclear.
Now, researchers at Yale School of Medicine have found the molecular regulators that orchestrate this delicate process. Their findings were published in Nature.
"Somatic hypermutation has always been the 'poor aunt' of immunobiology. For a while, the field was really stuck in making significant headway to understand the process," says David Schatz, Ph.D., chair and Waldemar Von Zedtwitz Professor of Immunobiology at Yale School of Medicine and senior author of the study.
Part of the challenge in studying somatic hypermutation has been the difficulty in controlling the mutation process so it could be studied experimentally.
"If you manipulated the genes in the cell, and the cell got sick, by the time you wanted to see what hypermutations occurred, the cell would have already died," Schatz says.
Adding to the mystery is that somatic hypermutations alter a single point on a single strand of DNA. How the enzyme responsible—called activation-induced deaminase (AID)—gains access to the single-strand DNA is unclear.
Exposing DNA to mutation
The answers to these questions began to emerge when Lizhen Wu, Ph.D., the first author of the study and an associate research scientist in Schatz's lab, successfully engineered a cell, called RASH-1C, that enabled the researchers to control and rapidly detect hypermutations. "Instead of waiting weeks for a mutation readout, now you have a system that gives you results in days," Schatz says. This got around the problem of cells dying too soon.
RASH-1C is derived from a type of cancerous B cell that Wu had modified a few years ago. Wu painstakingly scoured through every single gene in RASH-1C looking for the ones involved in somatic hypermutation. She did this by knocking out one gene at a time and analyzing how this affected somatic hypermutation.
Using information gathered from that effort, Wu focused her attention on proteins that control transcription, the process by which an enzyme called RNA polymerase II splits open double-stranded DNA and copies one of the strands into an RNA transcript.
Wu discovered that during somatic hypermutation, a protein called NELF (negative elongation factor) can "hitchhike" with RNA polymerase II into the area of the genes that encode antibodies and cause it to pause. That leaves part of the double-stranded DNA split open, exposing the single DNA strand.
"That opening creates an opportunity for AID to get in and mess with the DNA template," Schatz says. The researchers also found two other proteins—MLLT1 and MLLT3—that are responsible for drawing AID to the right region in the DNA. Without MLLT1 and MLLT3, somatic hypermutations are completely abolished.
The idea of a molecular agent that enables somatic hypermutation to take place was proposed by other scientists 30 years ago. "This study is taking us from an area of speculation to something much more concrete, with real evidence that this is happening," Schatz says.
Wu believes that NELF is not the only component that is causing the RNA polymerase II to stall. She is now looking into other molecules that may play a role in somatic hypermutation, with the aim of one day visualizing this process using high-resolution imaging techniques.
"If Lizhen can do that, it would be a gigantic advance for the field," Schatz says.
Publication details
Lizhen Wu et al., Transcription pause and elongation regulators mediate somatic hypermutation, Nature (2026). DOI: 10.1038/s41586-026-11092-4
Journal information: Nature
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