The body’s peacekeepers: how specialised immune cells keep a lid on inflammation

When the body encounters an infection, an army of immune cells is mobilised, each with a unique function. This includes the first responders that mount a generalised defence (innate immune cells like macrophages, dendritic cells and neutrophils), and those that contribute to our immune memory and enable us to respond more effectively during future infections (primarily T and B cells).

For immunologists like Carola Vinuesa, who leads the Crick’s Autoimmunity Laboratory, one type of immune cell remains elusive. “B-1 cells are innate-like B cells and exist in animals like mice, but their presence and function in humans remains an intriguing mystery,” she says.

“Think of them as the immune system’s peacekeepers that keep a lid on inflammation. Disruption in their development and function could contribute to autoimmune diseases or increased vulnerability to some infections.”

In research published today in Nature, Carola and her team at the Crick and former colleagues from Australian National University, showed how two proteins – TCF1 and LEF1, previously only studied in T cells – enable B-1 cells to apply the brakes on inflammation in mice and used this information to identify signs of B-1 activity in humans.

They found for the first time that the regulatory ability of a predominant subset of B-1 cells, called B-1a cells, is promoted by the expression of the transcription factors TCF1 and LEF1. These genes switch on anti-inflammatory programmes and support self-renewal of the B-1a population over time.

To better understand mechanisms of TCF1 and LEF1 expression, the team then used gene editing techniques to remove their expression in mice. They then tested the ability of B-1a cells to respond to autoimmune activity in the brain which could be compared to the neuroinflammation observed in multiple sclerosis (MS).

Qian (Sophie) Shen, first and co-corresponding author of the study, describes how removing the genes lowered the number of B-1a cells and also changed their behaviour: 

“Removing TCF1 and LEF1 in adult mice led to production of a smaller number of dysfunctional B-1a cells that failed to restrain an immune assault on the brain resembling MS.”

Sophie also observed that cells without TCF1 and LEF1 produced significantly less of an anti-inflammatory compound called IL-10, suggesting these genes help B-1a cells to regulate the immune system through production of IL-10. 

In the search for similar cells in humans, the team then analysed fluid that surrounds the lungs, called pleural fluid, from people with pleural infections, to see if any cells also expressed TCF1 and LEF1. They found an abundance of B-1-like cells, in the pleural fluid as well as the blood of some patients, and these cells expressed both genes.

They also detected expression of TCF1, LEF1 or both in malignant B cells in people with a type of blood cancer called chronic lymphocytic leukaemia (CLL). As these cancerous B cells express the same genes as B-1a cells in mice, the team believe this is further evidence for the existence of B-1-like cells in humans, as the healthy version of CLL cells.

“Our work has opened questions about how B-1a cells influence infections and cancer,” explains Sophie. “More research will be needed to understand which situations trigger B-1a cells to try to reduce inflammation and use this information to improve treatments or identify new markers of disease.”

“We’ve also established an intriguing link between their ability to self-renew and their peacekeeping functions,” adds Carola.

Carola also thinks that TCF1 and LEF1 could be harnessed to increase effectiveness of other immune cells. “We could potentially boost B cell memory and potential to self-renew, improving the body’s response to pathogens or vaccines.”

Carola and Sophie worked with the Genetic Modification Service, the Biological Research Facility, the Flow Cytometry team and the Genomics team at the Crick. Key contributors were Nikolaos Kanellakis from CAMS Oxford Institute and the School of Infection and Helen Parry from Inflammation and Immunology at the University of Birmingham who helped investigate pleural infection and CLL patients’ samples respectively.