Scientists at the MRC HIU and the Garvan Institute of Medical Research (Sydney, Australia) have defined the origin and behaviour of an enigmatic macrophage population that is responsible for clearing potentially harmful by-products generated when the immune system tailors its antibody response to infection and vaccination. The study, published in the journal Cell, tracked down where these macrophages originate, and how they function to clear cellular ‘garbage’.
Antibodies are large proteins that play a key role in in the body’s immune response: antibodies target foreign bodies and stop them working and/or target them for clearance. Each antibody has specificity – meaning that it should bind only to the particular target (pathogen) it is raised against – and each needs to bind with a certain strength (affinity).
Antibodies are made by B cells, a type of white blood cell. Dr Oliver Bannard, who led the Oxford arm of the work, explained “Everybody has about 5-10 billion B cells circulating through their lymph tissues and blood, each capable of expressing a unique antibody if needed.
“This provides the body with an enormous repertoire of antibodies to call upon during immune responses.”
“However, even this huge diversity of antibodies is not enough to guarantee a strong enough immune response against the almost infinite number of pathogen-derived molecules we may face in a life-time, and so the immune system developed a rather unique skill – it can trigger B cells whose antibodies bind the antigen but with low strength to “evolve” their antibody and make it better.” This is known as antibody affinity maturation.
Antibody affinity maturation relies on a cascade of enzymes that randomly mutate the antibody’s genes. This is because very occasionally, a mutation introduced in this way will improve how well an antibody binds to what it is targeting. To work properly, the immune system should then preferentially produce more of these B cells with enhanced antibodies – i.e., they need to be selected and expanded. Successful cells enter into more rounds of this enhancement cycle, iteratively improving the quality of the antibody response.
”Tingible body macrophages were described as far back as the late 19th century– they engulf so much debris from dead cells that you can see them even with a basic microscope. But more than a hundred years later, scientists still didn’t understand how these cell work – until this study. - Dr Oliver Bannard
Dr Bannard says “The problem is that inducing random mutations has a far greater chance of harming antibody function than improving it, and so cells acquiring less useful mutations also need to be quickly removed from the response. Failure to properly remove the debris left over after cells die can lead immune responses to target cells from the body itself (or parts of them), ultimately causing autoimmune diseases.”
Clearing these debris is a major challenge for the immune system- about half of all responding B cells (i.e., thousands of cells) die every ~5-6 hours, and clearing away these dead cells is important.
The cells responsible for this kind of dead B cell garbage clearance are called tingible body macrophages.
”These cells were described as far back as the late 19th century– they engulf so much debris from dead cells that you can see them even with a basic microscope,” said Dr Bannard.
“But more than a hundred years later, scientists still didn’t understand how these cell work – until this study, it has not been clear where they come from when the immune response starts, what cues trigger their development, or how they behave in order to ensure such efficient dead cell clearance. “
The research team gained an initial clue from parallel experiments that they performed revealing that tingle body macrophages ultimately develop from cells already present in the lymph nodes before the immune response starts – i.e., their development does not depend on white cells from the blood being called upon.
But lymph nodes are complex, made up of millions of cells, making it difficult to find which cells exactly are giving rise to these special macrophages. Dr Bannard said “ Working with our colleagues in Australia, we used a combination of techniques to look for a precursor needle in the lymph node haystack: cutting-edge imaging, fluorescent reporter and genetic temporal lineage tracing approaches helped us find a precursor cell that turned out to be hiding in plain sight.”
The research team found a that a previously overlooked group of macrophages sparsely populate the lymph node section where resting B cells live, and are capable of proliferating and maturing into tingible body macrophages if and when needed. The team tested the importance of these cells by inducing cell death (using a laser or a targeted toxin treatment), and then tracking how macrophages reacted – this revealed a striking transformation from resting to active in B cell follicle macrophages.
The team also used live imaging to find that while resting and mature tingible body macrophages remain static in one place, they extend long ‘arms’ (visible in main image: the green spots are tingible body macrophages, with holes that are vacuoles full of apoptotic debris. ) that track down and chase their targets from quite some distance.
This research was carried as a collaboration between Veera Panova (Bannard Lab) at the MRC WIMM and Abigail Grootveld and Wunna Kyaw (Phan Lab) at the Garvan Institute.
Read the full paper in Cell.