Uncovering how the body's specialized immune cells control inflammation

Have you ever wondered why some people seem naturally immune to certain bacterial infections? Or why do some recover quickly even after exposure to viruses? The answer may be a mysterious group of immune cells in our bodies called B-1a cells. For a long time, scientists have even debated whether humans actually possess these cells.

Now, in a study published in the international journal Nature, titled "TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function," scientists from the Australian National University and other institutions not only confirm the existence of human B-1a cells but also reveal how two key transcription factors—TCF1 and LEF1—act like "commanders" to regulate the survival and function of these cells. This research not only solves a mystery in immunology but also provides new insights for future treatments of autoimmune diseases, chronic infections, and even cancer.

B-1a cells are a type of innate immune-like B cell, primarily located in serous cavities such as the chest and peritoneal cavity. They rapidly produce natural antibodies to recognize pathogens such as bacteria and viruses. They also secrete anti-inflammatory factors such as IL-10, exhibiting immunomodulatory functions that help prevent excessive inflammation and autoimmune diseases. However, whether these cells actually exist in the human body, how they are maintained, and how their functions are regulated have been a source of controversy in immunology.

In this study, researchers aimed to uncover the "command system" behind B-1a cells. They focused on two transcription factors, TCF1 and LEF1. These two factors are known to regulate stem cell properties in T cells and stem cells, but their roles in B cells remain unclear. Therefore, the researchers sought to determine whether TCF1 and LEF1 are also expressed in B-1a cells and whether they influence B-1a cells' development, maintenance, and function.

Figure 1. TCF1 and LEF1 are required for B-1a self-renewal. (Shen Q, et al., 2025)

The researchers first analyzed B cells in the mouse peritoneal cavity using single-cell RNA sequencing. They found that TCF1 and LEF1 were indeed highly expressed in B-1a cells. They then constructed a mouse model with B cell-specific TCF1 and LEF1 deficiency and performed cellular phenotypic analysis. The results showed that the number of B-1a cells in the double-deficient mice was significantly reduced, particularly in the peritoneal cavity and spleen, where the number of B-1a cells decreased by over 70%. Through cell transplantation experiments, B-1a cells lacking TCF1/LEF1 were transplanted into immunodeficient mice. They observed that these cells were unable to effectively colonize and proliferate, indicating that their self-renewal capacity was impaired. Subsequently, through RNA sequencing and metabolic pathway analysis, they found that in B-1a cells lacking TCF1/LEF1, MYC-dependent metabolic pathways were inhibited, resulting in excessive cell proliferation but functional "exhaustion," and decreased expression of immune regulatory molecules such as IL-10 and PD-L1. Researchers reported that they also found B-1-like cells expressing CD5, CD43, TCF1, and LEF1 in the pleural effusion and blood of pleuritic patients. These two factors were also highly expressed in chronic lymphocytic leukemia (CLL) cells.

Researchers have shown that TCF1 and LEF1 are key factors in maintaining B-1a cells' stem cell properties and immune regulatory functions. By promoting the MYC pathway and IL-10 secretion, they help B-1a cells maintain a quiescent state after activation, preventing excessive proliferation and functional exhaustion. The absence of these two factors not only reduces B-1a cell numbers and impairs their function, but also makes them unable to effectively suppress brain inflammation.

Excitingly, this study is the first to clearly identify B-1-like cells in humans and suggests they may play important roles in infection and cancer. For example, in patients with pleurisy, these cells comprise up to 80% of pleural effusions, suggesting they may play a crucial role in local immune regulation. This study not only resolves a long-standing scientific controversy but also provides a new perspective on the fine-tuning of the immune system. TCF1 and LEF1 act as the "twin engines" of B-1a cells, controlling their survival and renewal as well as their immune regulatory functions. This discovery has broad potential applications for future research on a variety of diseases, including autoimmune diseases and cancer.

Reference

Shen Q, et al. TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function. Nature, 2025: 1-10.