Immune cells flock like birds

Picture a flock of birds in the sky. Then imagine how the entire flock changes direction at the same time, without any bird telling all the others what to do.

This kind of coordinated movement between many individuals is common in nature, including birds flocking, fish schooling and insects swarming.

It is also present in the human immune system, with the immune cells swarming around a wound to kill millions of invading bacteria.

Now researchers have discovered how the immune system is coordinated so that only exactly the necessary number of immune cells reaches the wound.

“When you cut yourself, the immune cells in the immediate surroundings react to the threat from bacteria, but so do immune cells far from the wound. They flock to the wound, and this study showed how this flock response is regulated when no central command controls it all,” explains Orion Weiner, Professor, Cardiovascular Research Institute and Department of Biochemistry and Biophysics, University of California San Francisco, United States.

The research, with Evelyn Strickland from Orion Weiner’s laboratory as first author, has been published in Developmental Cell.

Just enough

Every time you are wounded, your immune system must respond, but some mechanisms behind the immune reactions have long been a mystery, such as neutrophils, which flock to a wound to contain any threats.

The immune response must be very precise to avoid having too few or too many neutrophils arrive at the wound. Too few neutrophils provide an insufficient immune response to limit the spread of pathogens, whereas too many can damage the tissue they are trying to protect and can lead to excessive inflammation.

How does the immune system ensure that the precise number of immune cells needed arrives?

“The challenge has been understanding how the system gets just the right number of cells to respond when no one is counting,” says Orion Weiner.

Like a stadium wave

Immune cells are clearly recruited to a wound through intercellular communication. The cells immediately around the wound tell the neighbouring cells to come to the wound, and those cells tell their neighbours and so on.

This is similar to a stadium wave, in which one person starts the wave by standing up and then the next person does until the whole stadium is in motion.

The only difference is that the whole stadium is welcome to join in the celebration, whereas the human body needs a limited immune response, similar to stopping a wave when exactly 1,000 people are participating.

“The immune system has a control system to ensure that it does not just keep recruiting more and more cells to a wound, and our own experiments have shown that if this system malfunctions, the immune system cannot mount an appropriate response,” explains Orion Weiner.

Creating infections in a petri dish

To determine what happens in infection, the researchers created an experimental set-up with purified neutrophil cells from donors placed in a petri dish. In collaboration with Daniel Irimia from Massachusetts General Hospital in Boston, USA, the researchers used yeast cells to mimic an infection and then observed what the neutrophils did.

The researchers observed the movements of the neutrophils and, using special chemicals, caused the neutrophils to glow when they communicated with each other, enabling the researchers to visualise what happens when neutrophils flock to a wound.

Neutrophils radiate waves of signals

The study revealed how neutrophils radiate signals as pulsating waves while flocking to the threat – in this case, the yeast cells. When the signal waves hit the neutrophils, they begin to participate and amplify the signal further and further from the site of infection so that more and more cells flock towards the wound to fight the infection.

However, the extent of the waves is limited and is determined by an NADPH oxidase–based feedback loop such that when the signal between the cells reaches a certain strength, the cells in the front of the wave stop transmitting information, ending the signal wave and ensuring that the immune system does not overreact.

The researchers discovered this with the help of models developed by Ariel Amir from the Weizmann Institute of Science, Rehovot, Israel.

The experiments also showed that disabling this feedback loop removes the brakes on the immune system, which then continues to recruit more and more cells in an uncontrolled manner.

“In this experiment, we pared the system to the absolute minimum while still being able to observe the neutrophils swarming. In the body, where the neutrophils also communicate with other cells, more complex behaviour probably arises. The next step will be to investigate what happens when more immune cells are present and how other bodies than yeast cells can initiate an immune response,” explains Orion Weiner.

Associated with various diseases

Orion Weiner says that this research is generating knowledge about a well-functioning immune system but also about a dysfunctional one, which is the starting-point for developing various diseases.

Some diseases result from an insufficient immune response to an infection caused by errors in the processes that cause the immune cells to swarm. Other diseases can result from the immune system lacking brakes and therefore overreacting to an infection.

Chronic granulomatosis is an example of overreaction: defects in a mechanism that is supposed to end the immune system’s wave movements lead to inflammation in various organs because the immune system is overactive.

The researchers analysed neutrophil cells from these people in collaboration with Michael Mansour from Harvard Medical School and Christa Zerbe from the United States National Institute of Allergy and Infectious Diseases.

“The perspective of our research is that improving understanding of the mechanisms involved may enable us to modulate them so that we can increase the activity of the immune system in some cases and reduce it in others,” concludes Orion Weiner.