Researchers at the University of Liverpool and University of Nevada, Reno have helped uncover how the body adapts its immune defences during periods of increased demand, such as infection, inflammation and recovery following stem cell transplantation.
The study, published in the journal Blood, sheds new light on how the body controls neutrophils, a type of white blood cell that acts as one of the immune system’s first responders to infection.
Neutrophils are produced in the bone marrow and travel through the bloodstream to help fight bacteria, viruses and other threats. To reach sites where they are needed, neutrophils must first slow down and attach firmly to blood vessel walls before moving into the surrounding tissue. This process depends on specialised adhesion proteins on the surface of the cell.
The researchers focused on FERMT3, a gene that produces a protein called kindlin-3. Kindlin-3 plays a critical role in activating integrins, the adhesion proteins that enable neutrophils to grip blood vessel walls. Defects in FERMT3 cause a rare inherited condition called Leukocyte Adhesion Deficiency type III (LAD-III), in which immune cells cannot adhere normally and patients can suffer recurrent infections.
The team discovered that cells can fine-tune this adhesion machinery through a process called alternative splicing, which allows a single gene to produce slightly different versions of the same protein. In this case, this process inserts just four extra amino acids into kindlin-3.
Remarkably, this very small change makes kindlin-3 more effective at associating with the cell membrane, where it helps activate integrins. The longer form of kindlin-3 therefore enhances integrin activation and neutrophil adhesion. This is particularly interesting because this form of kindlin-3 had previously been considered non-functional.
The researchers also found that production of the longer kindlin-3 form is selectively increased during stress myelopoiesis, when the body rapidly produces and mobilises blood cells in response to infection, inflammation or recovery following stem cell transplantation. The findings suggest that alternative splicing provides a way for cells to fine-tune their adhesion machinery to meet changing demands placed on the immune system.
The study also provided an unusual opportunity for integrated master’s student Madeleine Vidal, who carried out key biochemical experiments during her MBiolSci project and is a joint first author on the paper. Madeleine said: “It was incredibly exciting to see experiments I carried out as part of my MBiolSci project contribute to this study. Being able to work alongside researchers in the lab and see the project develop all the way through to publication in Blood has been a fantastic experience.”
Professor Benjamin Goult, co-corresponding author of the study, said: “What I love about this finding is how small the change is. Alternative splicing adds just four amino acids to kindlin-3, yet those four amino acids change how effectively the protein is recruited to the cell membrane and help tune neutrophil adhesion. It is a beautiful example of how cells can make subtle changes to the same protein to adapt its function to different physiological demands.
“It has also been particularly rewarding to see Maddie make such an important contribution to the work during her MBiolSci project. Giving students the opportunity to participate in real, internationally collaborative research is a hugely important part of what we do at Liverpool.”
The findings could have implications for understanding immune recovery following stem cell transplantation and for improving knowledge of rare inherited immune disorders such as Leukocyte Adhesion Deficiency type III (LAD-III). Stem cell transplantation is a potentially life-saving treatment for patients with blood cancers and other serious blood disorders, and around 4,000 stem cell transplants are carried out in the UK each year. Understanding how neutrophil adhesion and mobilisation are regulated during recovery may help researchers better understand how the immune system rebuilds itself after stem cell transplantation.
The study, ‘FERMT3 alternative splicing enhances kindlin-3 membrane recruitment for neutrophil adhesion during stress myelopoiesis’, was published in Blood and involved researchers from the University of Liverpool, Dr Lai Wen and colleagues at the University of Nevada, Reno, and Klaus Ley at Augusta University.