Why Does Your Immune System Not Attack You?

Right now, inside your body, millions of immune cells are on patrol. These cells are ready to attack dangerous invaders like bacteria and viruses, helping protect you from diseases. Most of the time, the immune cells target germs while leaving your body’s healthy cells alone. How do they know what to attack?

The immune system learns to tell “self” (meaning what belongs in your body) apart from “non-self” (things that do not belong, such as bacteria, viruses, cancer cells, and other foreign stuff) through a process called immune tolerance. But how does the immune system learn the difference between self and non-self?

Immune cells do not start out knowing what to attack and what to protect—they must be trained. We will focus on T cells, which are a major type of immune cells important for recognizing invaders and coordinating immune responses. Immature T cells are produced in the bone marrow. They then travel to a small organ called the thymus, located just above the heart, where training happens. In the thymus, T cells that strongly recognize the body’s own “self” tissues are removed, while the remaining T cells are allowed to mature. These mature T cells leave the thymus as naïve T cells, meaning they have not yet encountered their specific target. Later, when naïve T cells recognize “pieces” of proteins from foreign organisms, they can become effector T cells that help fight infections. However, if naïve T cells are wrongly activated by self proteins, they can attack the body’s own tissues.

The filtering out of dangerous T cells, which is called central tolerance, reduces the risk that immune cells able to attack “self” ever enter the bloodstream—while still allowing a strong T-cell immune response to develop against invaders (Figure 1A).

The training in the thymus is not perfect, and some autoreactive T cells still slip through. So the body must rely on additional safety system that work later on, after T cells begin circulating through tissues and organs. To accomplish this, another class of T cells called regulatory T cells (Tregs) is generated in the thymus. Tregs exit the thymus and circulate through the body, providing additional protection from cells that recognize self tissues. This process is called peripheral tolerance (Figure 1B). Tregs keep the immune system in check and are critical for preventing damage to healthy organs and tissues.

Regulatory T Cells: The Immune System’s “Brakes”

When scientists first discovered Tregs in laboratory mice, they noticed something striking. When these cells were missing or did not work properly, the immune system spiraled out of control and the autoreactive T cell “escapees” began attacking the body itself, leading to autoimmune disease [1]. Around the same time, scientists discovered that a rare human autoimmune disease called IPEX is caused by a mutation in a gene that is essential for the development and function of Tregs [2, 3].

Because of this finding, Tregs were originally described as the immune system’s “brakes”. Just as brakes keep a car from speeding out of control, Tregs help calm immune responses, keeping other T cells from becoming too aggressive and damaging healthy tissues.

Tregs can use several tools to carry out this calming role. They can release chemical signals that tell nearby T cells to slow down. They can also communicate through direct cell-to-cell contact, almost like giving a stop signal face to face. In addition, they can “soak up” growth molecules that other T cells need to stay alive and active. These control tools overlap, so if one method is not enough, others can still help keep immune activity in check.

Tregs are Much More Than Just Brakes

As researchers studied Tregs more closely, they began to realize that describing them only as the immune system’s brakes was much too simple. In many situations, the immune system needs to do more than calm responses. After an infection or injury, inflammation needs to be controlled but, in addition, tissues must repair themselves, and normal function must return. Researchers discovered that Tregs play important roles in this recovery process—not only calming immune responses but also helping tissues heal (Figure 2) [4].

One of the clearest examples of Tregs supporting tissue healing comes from studies of muscle injury in mice. Experiments showed that Tregs are a critical part of this process. When Tregs were removed, healing slowed down and inflammation lingered. Importantly, Tregs’ repair role is completely separate from their immune-calming role. In these experiments, muscles failed to heal properly even when inflammation was kept under control.

Tregs can use different repair programs in different organs, including muscle, lungs, heart, brain, and skin. In each organ, they pick up local cues from surrounding cells and adjust their behavior to match what that organ needs. Basically, Tregs work closely with nearby cells as part of a local “recovery team”, taking on different roles depending on where they are located. Tregs help “teach” other immune cells to calm inflammation in that area. By spreading this calming state to other cells, Tregs can create a more lasting shift toward tolerance and complete healing.

Beyond supporting tissue repair, Tregs influence many other aspects of immune health. They help prevent the immune system from overreacting to harmless things in the environment, like food or pollen, and they support peaceful coexistence with helpful microbes that live in the gut. In mouse studies, researchers even discovered that some Tregs can produce molecules that the body turns into natural pain relievers. In other words, Tregs do far more than put the brakes on immune responses—they help guide recovery and keep the immune system working in balance across the entire body.

When Tregs Struggle

Tregs may be powerful, but they are not invincible. Tregs can become “worn down” when inflammation lasts for a long time, such as after repeated infections, ongoing tissue damage, or long-term stress. Instead of acting as effective brakes and repair helpers, some may lose their regulatory abilities or even start attacking healthy tissues. When Tregs cannot do their jobs properly, the immune system can remain stuck in a low-level state of alarm, and damaged tissues may not heal well. Some people also have genetic differences that make their Tregs weaker. Aging can increase this challenge.

Tregs and Cancer: Too Much Calm?

Cancer begins when the body’s own tissue cells start growing in abnormal and uncontrolled ways. The immune system often recognizes these abnormal cells as a problem and destroys them. However, tumors also attract large numbers of Tregs [5]. Once inside a tumor, Tregs can shut down nearby immune cells and reduce their ability to fight the cancer. Some cancer treatments aim to reduce or block Tregs inside tumors, allowing the immune system to fight back more strongly. This approach has helped shrink cancers in certain patients. However, removing too many Tregs can be risky, since it may lead to harmful immune attacks on normal tissues. Scientists now face a delicate challenge: learning how to decrease Treg activity in tumors while preserving their protective role elsewhere in the body. Solving this problem could make cancer treatments more effective, while keeping the immune system balanced.

Using Tregs as “Living Medicines”

In some medical situations, doctors need to step in to stop the immune system from causing harm to the body. You may have heard of conditions such as type 1 diabetes, multiple sclerosis, or rheumatoid arthritis, for example. A similar problem can happen after an organ transplant. Even though a donated kidney or heart is meant to save someone’s life, the immune system can see the organ as a foreign intruder and try to destroy it.

To prevent this kind of damage, doctors often help patients manage their symptoms with medicines that turn the activity of the entire immune system way down. While these medicines can be lifesaving, they also make it harder for the body to fight infections, heal from injuries, or recover fully. Because Tregs naturally help calm immune responses and support tissue repair, scientists began asking whether these cells could be used as “living medicines” to guide recovery more precisely instead of shutting down the entire immune system [6].

In early studies, doctors collected Tregs from patients who had received organ transplants or from children recently diagnosed with type 1 diabetes. They grew more of the Tregs in the laboratory and then returned them to each patient’s body (Figure 3A). These first tests showed that this approach was safe and, in some cases, it also reduced harmful immune activity and protected healthy tissue [7].

However, these early treatments had limits. The Tregs used in these studies were not directed to specific organs, so many did not reach the tissues that needed help. Some Tregs did not survive long enough or remain active long enough to keep harmful immune activity under control over time.

To address these limits, scientists are now developing ways to give Tregs clearer instructions (Figure 3B). Some Tregs are being designed to “see” cells or proteins in the specific tissues that are under attack, helping them work specifically in problem areas. Other cells are being adjusted to function better in damaged or inflamed environments and to stay active longer once they arrive. By engineering Tregs with these tissue-specific abilities, researchers hope to create treatments that work more precisely and are more effective.

Overall, instead of turning down the entire immune system, using Tregs as “living medicines” could help the immune system calm itself in the right places and at the right times, while still allowing the body to fight infections and repair damaged tissues.

A New Way to Think About Treating Disease

Research on Tregs is changing how scientists think about the immune system. The immune system is not just a defense force against germs—it also helps maintain tissue health and repair damaged tissues so the body can recover after illness or injury. Scientists are still learning exactly how Tregs work in different parts of the body, but these discoveries are already pointing toward new kinds of treatments. Instead of turning down the entire immune system, doctors may one day use Tregs as “living medicines” to calm harmful immune responses in specific tissues. This approach could help treat autoimmune diseases, protect transplanted organs, and possibly even help keep people healthier as they get older. By learning how to guide these natural regulators, scientists hope to restore and strengthen the body’s own systems—reducing damage while preserving the ability to fight infections and repair itself.

Glossary

Immune Tolerance: ↑ The ability of the immune system to recognize the body’s own tissues and avoid attacking them while still responding to harmful invaders like bacteria and viruses.

Effector T Cells: ↑ T cells that can actively respond to threats by attacking infected cells or helping coordinate other immune cells during an immune response.

Central Tolerance: ↑ The process in the thymus where developing T cells that strongly recognize the body’s own tissues are removed before they can enter the bloodstream.

Autoreactive T Cells: ↑ T cells that mistakenly see the body’s own tissues as a threat and can attack them if they are not controlled.

Regulatory T Cells (Tregs): ↑ A special type of T cell that helps keep the immune system balanced by calming immune responses and preventing damage to the body’s own tissues.

Peripheral Tolerance: ↑ Safety systems throughout the body that control immune cells after they leave the thymus, often using regulatory T cells to prevent damage to healthy tissues.

Autoimmune Diseases: ↑ Diseases that occur when the immune system mistakenly attacks the body’s own tissues, damaging organs or causing long-lasting inflammation.

Inflammation: ↑ A protective response in which immune cells become active to fight infection but can damage tissue, often causing redness, heat, swelling, or pain.

Conflict of Interest

JB and FR are co-founders and hold equity in Sonoma Biotherapeutics. JB is on the Board of Directors of Gilead Sciences.

Acknowledgments

We wish to thank Dr. Susan Debad for providing us with a first draft and for her continued collaborative input. We would also like to thank the coauthors of the original manuscript: Megan K. Levings, Alexander Y. Rudensky, Qizhi Tang, and Piotr Trzonkowski.

AI Tool Statement

The author(s) declared that Generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.