HMN 2026: How Robust flu protection may rely on B cells that are long-lived residents in the lungs

Deep in the lungs, resident memory B cells stand guard against influenza reinfection—but whether they remain there may depend on how strongly they are signaled through their own receptors. New research using an animal model of influenza infection provides fresh insight into how these cells form and persist, findings that could inform the design of vaccines aimed at strengthening immune defenses in the lungs.

In a study conducted at Washington University in St. Louis, Missouri, investigators report in Science Immunology that the magnitude of B cell receptor signaling plays a central role in determining whether B cells establish themselves as long-lived residents in the lungs.

“Lung tissue-resident memory B cells are important in establishing protective immunity against respiratory pathogens,” wrote Dr. Kumari Anupam, lead author of the investigation, which essentially determined how these cells accumulate and produce a shield against future infections.

Distinct cells in the lungs

Lung-resident memory B cells—referred to as B_RM cells—are both phenotypically and transcriptionally distinct from circulating memory B cells, the researchers found. In the animal model, these cells were stably maintained for at least six months after influenza infection.

“Lung B_RM cells develop during the first two weeks after infection in a process dependent on the presence of local antigen and T cell help,” Anupam explained in the research paper, but noting that the pathways regulating the accumulation of resident B memory cells in lung tissue had remained poorly understood.

Seeking insight, the team examined the mechanisms that determine the formation of lung-resident B memory cells and were able to advance a deeper understanding of immune activity in the lungs following pathogenic infection. Investigators identified the essential drivers underpinning how abundantly—or sparingly—resident memory B cells accumulate in the respiratory tract.

Signaling vigor shapes residency

The St. Louis-based researchers turned to a CRISPR-Cas9 screen in a mouse model of influenza infection to identify transcription factors that influence B_RM cell development.

They found that the strength of signaling through the B cell receptor was a key determinant of whether B cells took up residence in the lungs.

Transcription factors, such as NFATC1—nuclear factor of activated T cells 1—and EGR2, early growth response 2, acted to suppress B_RM cell accumulation, while IKZF1, which stands for IKAROS family 1, enhanced it. Notably, increasing IKZF1 expression—despite its role as a negative regulator of B-cell receptor signaling—or inhibiting mTOR signaling promoted the formation of lung-resident B cells. The master regulator known as mTOR, governs cell growth, proliferation, survival and transcription.

Together, the findings point to the BCR–mTOR signaling axis as a critical regulator of mucosal immunity following respiratory infection.

“We found that the magnitude of BCR signaling received by a B cell regulates its ability to establish residence within the lungs after influenza infection,” Anupam said.

Implications for vaccines

Earlier research had suggested that circulating memory B cells migrate to the lungs in response to local cues, but the signaling pathways guiding that process were unclear.

By identifying the molecular mechanisms that control B_RM cell formation, the new study provides a clearer paradigm for understanding how long-term immunity is established in the respiratory tract.

The findings suggest that dialing down signaling through the B cell receptor—rather than amplifying it—may help promote the development of these protective resident memory B cells.

That insight could prove important for vaccine design. Instead of focusing solely on generating circulating antibodies, future strategies might aim to position immune cells directly within lung tissue, where respiratory infections take hold.

Such approaches could enhance protection against influenza and other respiratory viruses by strengthening immune defenses at the site of infection.

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