To Be Naive or to Remember: That Is the B Cell Question

Human Technopole researchers have identified the molecular programmes that drive human B cell differentiation after activation, shedding new light on how the immune system balances rapid defence with long-term protection. The findings are published in Molecular Systems Biology.

When the body encounters a virus or vaccine, B cells are among the immune system’s most important responders, helping protect us by producing antibodies. But not all B cells are the same. Naive B cells have not yet encountered a given infection or vaccine target. Memory B cells, by contrast, are the product of earlier immune responses: they have seen a pathogen before and are primed to respond more quickly if it returns.

During infection or after vaccination, these two B cell populations can follow different paths. Some become plasma cells, which rapidly produce large amounts of antibodies, while others enter germinal centres, specialised sites in lymph nodes where B cells refine their antibodies and help build long-term immune protection.

Longstanding questions in immunology are how B cells make this choice, and whether naive and memory B cells follow different rules when they do so. The group of Blagoje Soskic at Human Technopole addressed these questions by mapping the gene-control programmes that guide human B cells as they activate and differentiate.

Using single-cell sequencing, the researchers tracked nearly 119,000 human B cells over time after activation. They found that, at the earliest stage of activation, naive and memory B cells show broadly similar patterns of gene activity, but their paths soon diverge. Memory B cells were strongly biased towards becoming plasma cells, the antibody factories of the immune system. Naive B cells, by contrast, split into two distinct paths: some moved towards becoming plasma cells, while others adopted features of germinal centre B cells. This suggests that memory B cells more readily adopt the plasma-cell fate, while naive B cells retain greater flexibility.

At the heart of this decision is a competition between different gene regulatory networks, controlled by key transcription factors. The study identified IRF4 as a key driver of the plasma-cell pathway, especially in memory B cells, where its activity rose early and remained high. In naive B cells, IRF4 increased only transiently, and cells followed different fates depending on whether that signal was maintained. Another regulator, SPI1/PU.1, showed the opposite pattern and was linked to the germinal centre route. The balance between these opposing programmes appears to help determine whether a B cell becomes an antibody-producing plasma cell or takes the germinal centre path.

The researchers then tested this model directly using CRISPR gene editing. When they switched off IRF4, cells not only struggled to become plasma cells, but also failed to develop a normal germinal-centre-like programme. By contrast, switching off another key gene in the same pathway, PRDM1, strongly reduced plasma-cell development. These experiments showed that PRDM1 is crucial for generating plasma cells, while IRF4 has a broader coordinating role, influencing both plasma-cell differentiation and the proper development of germinal centre states.

The researchers also found that some features of B cell behaviour can be passed on when cells divide. By tracing clonally related cells (i.e. cells descended from the same original B cell), they found that sister cells often shared similar expression patterns, especially for genes involved in plasma-cell function. To test this idea, the researchers trained machine-learning models on their data and found that related cells could often be recognised from their gene-expression patterns alone. This suggests that some aspects of B cell behaviour are not decided anew in every cell, but can be passed on across cell divisions as heritable transcriptional states.

Together, these findings provide a clearer picture of how human B cells make fate decisions. They show that naive and memory B cells are not simply slower and faster versions of the same response, but are guided by different molecular programmes. By identifying the molecular switches that favour one immune outcome over another, this work could help researchers better understand vaccination, infection, and autoimmune disease, and may eventually inform strategies to steer B cells towards more protective responses.

Demela, P., Esposito, L., Marchesan, P. et al. Competing gene regulatory networks drive naive and memory B cell differentiation. Mol Syst Biol (2026).

https://doi.org/10.1038/s44320-026-00207-8