by Haim Moore
figures by Rebecca Senft

How familiar are you with your immune system? You might be aware of its role in protection from external threats, but what if I told you that it does a lot more behind the scenes? New research is shedding light on how your immune system carries out several unexpected functions in your body, including repairing wounds post-injury and controlling the performance of organs that you may not have associated with your immune system before. 

A simple race car analogy is often used in clinics to describe to patients how the immune system operates. The analogy uses an accelerator pedal to activate immunity and a brake pedal to stop the immune response when it’s no longer needed. Picture the immune system helping us win the race against invading microbes then halting the response when it’s no longer needed. But for that analogy to stay true to the new functions we’re discovering in the immune system regarding repair and organ-specific function, we must tweak it to include reversible gears and pit stops. With these features, we see that the immune system isn’t just gunning for a full-throttle Formula One sprint. Rather, the immune system is channeling Ford v. Ferrari at the 24 Hours of Le Mans, the oldest endurance race in the world.  

The spectrum of immunity: the old race car model

We know best of all that the immune system is critical for protecting us from foreign invaders like viruses and bacteria. To this end, the immune system utilises physical barriers, surveillance systems, and specialized cells for microbial clearance. You may personally experience your immune system‘s defense mechanisms as the headache and swelling you feel when you get sick with a cold. These are all side effects of inflammation, which is the process of mobilizing your immune cells to eliminate harmful microbes. We meet invading mayhem with internal mayhem. The key ingredient in inflammation is damage – both to enemy microbes and to your body. 

With its go and stop pedals, the race car I’ve described for you so far either moves forward or slows to a stand-still. But inflammation is damaging to our own cells too. If we didn’t find a way to reset to the starting line, we wouldn’t be ready to take on the next pathogen that comes our way. It turns out that our immune system also has regulatory mechanisms for repairing and resetting.

Turning destruction into creation: driving the race car in reverse

When you recover from sickness, you feel better. This process is not simply the removal of infection – it’s the active process of repairing the collateral damage inflicted on our bodies over the course of fighting an infection. A whole wing of the immune system shuts down inflammatory pathways and activates alternative pathways associated with repair. For example, some immune cell types called macrophages clear dead cells and other debris post-inflammation. Similarly, race cars break down with use. Clearing debris and repairing automotive parts is essential for continued race car performance (Figure 2).

Remember, now we’re looking at this like an endurance race, not a sprint. The finish line is set at wherever you can outpace your opponent. That means your immune system might catch up to and thwart an invader long before finishing a full loop of the race track and reaching the end of the course. Finishing the course could result in increased cumulative damage to the race car. In this case, it makes more sense for your race car to get back to the starting line by going backward, instead of finishing the loop forward. Here’s where our new concept of a reverse gear comes in. The immune system drives backward as it interacts with surrounding cells to initiate repair and clear debris.

Location, location, location: Immune cell setting defines function

The goal of a race car is to stay ahead of the pack. That means accelerating quickly in order to outrun the opposition without crashing and burning, and then preparing to be able to do it all over again. But not all races run without a hitch, and race cars sometimes need to upgrade different parts to match the race conditions. Here’s where the pit stop crew comes into play. A team’s pit crew services the vehicle in the pit stop, a specialized checkpoint in the race track, as quickly as possible, completing a number of critical processes like changing tires or refueling. Likewise, your body is vast, and different tissues have special requirements for physical barriers, surveillance, and clearance by the immune system. Imagine that the immune system race car team has pit stop crews dedicated to specific organs (Figure 3).

These pit stop crews are highly specialized in what they do, based on where they’re in action. The immune pit stops in your gut, for example, differ from the ones found in your skin. In the skin, immune cells have become specialized to talk to hair follicle stem cells. When these immune cells are missing, hair growth ceases. In the gut, immune cells are specialized to communicate with neurons that regulate peristalsis, which is the wave-like muscular contractions used to move contents through your digestive tract. In your fat tissue, immune cells talk to surrounding fat cells to tell them how much energy to burn, affecting metabolism throughout your body. 

Repair is fundamental to the immune system

The more we look, the more we find the immune system playing unexpected roles in maintaining normal bodily functions. Disrupted immune pathways for repair and location-specific functions have already been implicated in disease. We should strive to study this axis of immunity further in order to leverage that knowledge to help patients. 

Our immune system is more than a Go Kart with start and stop pedals. It’s akin to the highly specialized teams of race cars and pit crews in professional endurance races. Immune cells protect you from the outside world and can produce immense amounts of damage to that end, but they also create an equal amount of repair and physiological equilibrium through post-injury tissue repair and particular location-dependent functional adaptations. Without these specialized functions, we would succumb to diseases faster, have a shorter life expectancy, and generally be able to do less with the life we have. 

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Haim Moore is a first-year Immunology MMSc student at Harvard Medical School who studies inflammatory cell death and inflammasomes. 

Rebecca Senft is a fifth-year Program in Neuroscience Ph.D. student at Harvard University who studies the circuitry and function of serotonin neurons in the mouse.

Cover image: “File:1966 24 Hours of Le Mans 11 (4771563706).jpg” by ZANTAFIO56 is licensed under CC BY-SA 2.0 

For More Information: 

• Check out this review about the emerging roles of the immune system beyond host defense.
• Check out this review about the cell circuits of macrophages in tissue repair.