How Does the Immune System Tell 'Self' from 'Other'? — Guards at the Gate, and a Patrol That Remembers Faces

A Splinter in the Finger

A wooden splinter got stuck in a finger and then came out. After about a day, that spot swells up a bit and turns red. When pressed, it throbs and is slightly warm. After a few days, it usually subsides.

Every day, we breathe, eat food, and grab doorknobs. Each time, we encounter countless tiny, invisible creatures. Even so, most days we do not hurt.

This means that somewhere inside the body, those encounters are being sorted out one by one. This article follows how the body distinguishes "me" from "others." The guards protecting the gate and the patrol that remembers a face it has seen once appear in turn.

The First Gate: Skin and Mucous Membranes

The thorn pierced through the wall known as the skin. The body has physical walls that block infection, and once those walls are breached, the immune system defends the body from that point on (PMID 39702433). The immune system is a network of cells and substances that recognizes and blocks intruders like bacteria and viruses that enter the body. Surfaces of the body that touch the outside, such as the skin and the inner walls of the intestines, are important defense lines that prevent microorganisms from digging into the body (PMID 22044254).

A mucous membrane is a thin, moist layer covering passages that run inside the body, such as the nose, mouth, throat, and intestines. Because the skin and mucous membranes meet the outside, they are covered with special cell layers to act as walls (PMID 12065907). However, mucous membranes are also where nutrients are taken in and waste is sent out. Therefore, they cannot simply be walls that block everything; they must let the right things in while blocking intruders (PMID 12065907). The walls themselves play a part in defense as a component of immunity. The surface of the mouth's mucous membrane has oily components that suppress microorganisms (PMID 23320785).

On top of those walls, there are also many microorganisms that naturally live there. On surfaces that touch the outside, such as the intestines, airways, and skin, bacteria that have evolved alongside humans live. These usually do not cause trouble, but if conditions change, they can cross the body's defenses and cause disease (PMID 15158604). Therefore, mucosal immunity handles two tasks together. It tolerates harmless foods, substances in the air, and resident microorganisms, while blocking intruders (PMID 15158604). What gut-dwelling microorganisms do is covered in "What Do Gut Microbes Do? — Guests Who Eat the Leftovers, Guests Who Hold the Room".

The body's first gates are the skin and mucous membranes, and these gates choose what to let in and what to block.

The Guard Inside the Door

When microbes enter the body, moving cells like white blood cells in the blood gather, swallow, and destroy the microbes. This was said by Russian biologist Ilya Mechnikov in his 1908 Nobel Prize lecture in Physiology or Medicine. He called these cells by a name meaning "eating cells" (PMID 15580257).

Phagocytes are immune cells that swallow and destroy whole microbes or the debris of dead cells. Phagocytes are the hands of the guard that first confront the threat inside the door. Innate immunity is immunity we are born with, which reacts within minutes to hours even to a first-time intruder. Innate immunity is the first immune system to face invading microbes, starting within minutes to hours after being attacked (PMID 30263032). It is a very old defense method, and most multicellular organisms have it (PMID 10719670).

Macrophages are large phagocytes that settle down and live in each tissue of the body. Macrophages are present in every tissue of the body. Their job does not stop at clearing microbes; they recycle iron, guard the walls lining the body's borders, and coordinate the healing of wounds (PMID 42726407).

Neutrophils are phagocytes that circulate in the blood, get called to the site of infection, and swallow microbes. Bacteria that have entered deep into the lungs are cleared together by two types of phagocytes: the macrophages living in that spot and the neutrophils called in from the blood (PMID 10719666).

Not all bacteria are swallowed quietly. Tuberculosis bacteria enter inside phagocytes and use those cells as their own home (PMID 25703560). How well phagocytes like macrophages and neutrophils trap and destroy these bacteria decides whether the infection takes hold at the start (PMID 25703560). The story of how the body traps tuberculosis bacteria for a long time continues in "What Is Tuberculosis? — The Sleeping Ember, and the Fire That Takes Months to Put Out".

Innate immunity is a guard we have from birth, and its hands are the cells that swallow.

What Do Guards Look For to Recognize Others?

A guard does not know the face of a first-time intruder. Then what do they look for to spot a suspicious person? In 1989, the American immunologist Charles Janeway Jr. offered an answer. It was the idea that immune cells must have a detection device that recognizes molecular structures commonly found in microbes (PMID 31499098).

Pattern recognition receptors are detection devices that recognize molecular patterns commonly found in bacteria or viruses, and are possessed by immune cells and mucosal cells. This pattern is shared by a large group of microbes. Therefore, the body uses this device not only to know that a microbe has entered, but also roughly what kind it is (PMID 10719670). This device is engraved in our genes from birth, and its variety is fixed. Because it recognizes molecules that microbes make and the human body does not, the body uses this to separate "others" that cause infection from "self" that is unrelated to infection (PMID 11861602). It is like a guard not knowing faces, but recognizing the attire worn only by intruders.

Toll-like receptors are a well-known group among pattern recognition receptors, named because they resemble Toll, a defense protein in the fruit fly. In 1997, Janeway and Ruslan Medzhitov, an immunologist from Uzbekistan in his lab, discovered this protein in humans. It was a human protein resembling the protein Toll, which turns on defense responses in fruit flies. When this protein, changed to a constantly turned-on state, was put into human cells grown in the laboratory, signaling substances that sound the alarm and molecules needed to awaken the immunity that selects and grows according to the met opponent were produced (PMID 9237759). The discovery of Toll-like receptors is counted as an event that changed the view of innate immunity (PMID 22539282).

Guards do not only look at microbes. They also recognize substances released by injured or dying cells, and alarms ring then as well (PMID 31558839). This alarm, which rings at an injured site without infection, is important for repairing and reviving tissue, but it also leads to various inflammatory diseases (PMID 31558839). One review considers Janeway's explanation to be largely correct, while adding that immunity also reacts strongly to these danger signals emitted by injured and stressed cells. The same review considers that such inflammation must be strictly regulated so that it does not spread to autoimmunity (PMID 25037632).

Instead of the intruder's face, the guard moves upon seeing patterns possessed only by microbes and signals emitted by injured cells.

Alert, Inflammation

The swelling and redness where a thorn has lodged is an alarm raised by the guards. Inflammation is a response where the body mobilizes immune cells, swells the area, and reacts against stimuli such as damage, infection, or foreign substances entering from outside. When pattern recognition receptors detect an intrusion, signals cascade within the cell. At the end of that chain, inflammatory molecules that coordinate the task of eliminating microbes and infected cells are produced (PMID 20303872).

Cytokines are small protein signals that immune cells send and receive to summon or wake other cells. When Toll-like receptors encounter a microbe's pattern, cytokines that call for inflammation are produced (PMID 11861602). Immune cells circulating in the blood cling to blood vessel walls and gather at the infected site by following the concentration gradients created by substances like cytokines (PMID 10719666). When the alarm rings, reinforcements find their way there.

This alarm is immensely useful. Sudden inflammation clears away microbes and subsequently opens the path to tissue repair. However, a balance must be struck between the defensive force and the damage that excessive inflammation leaves on surrounding tissues (PMID 36614083).

The alarm also has a process for turning off. The subsidence of inflammation is a process the body runs on its own, preventing inflammation from becoming excessively prolonged or intense (PMID 33915177). In this phase, neutrophils are prevented from gathering further, and macrophages clean up dead neutrophils, debris, and microbes (PMID 33915177).

Inflammation is an alarm raised by the guards, and turning off that alarm in a timely manner is also something the body does.

A Patrol That Remembers Faces

When meeting the same opponent a second time, the body confronts it faster and more efficiently than the first time (PMID 30263032). The second layer is mainly responsible for this work. Adaptive immunity is immunity that selectively recognizes a specific opponent, remembers the met opponent, and reacts faster and more efficient in the next meeting. Adaptive immunity operates by relying on a specific target possessed by the opponent and produces a response tailored to that target (PMID 30263032).

An antigen is a target recognized by immunity, usually a part of an intruder or an outside substance. If security looks at clothing, the patrol looks at faces. Each patrol member is tuned to only one different face.

A T cell is a white blood cell that checks protein fragments caught on the surface of other cells to recognize intruders or infected cells. Some T cells directly eliminate infected cells, and others guide the work of other immune cells (PMID 34859450).

One of the cells that receives that guidance is a B cell. A B cell is a white blood cell that makes antibodies, with a single cell making only antibodies that fit one target. The helping side of T cells coordinates the work of B cells making antibodies (PMID 34859450).

An antibody is a Y-shaped protein produced by B cells that sticks precisely to a specific target. How antibodies prepare so many shapes in advance is followed by "What Is an Antibody? — Millions of Keys Cut in Advance, and the Ones That Fit".

The two layers do not play separately. Innate immunity responds quickly while also helping adaptive immunity grow (PMID 39702433). For adaptive immunity to begin, cells presenting antigens must release molecules and cytokines that wake up T cells (PMID 9237759). For the patrol to move, news from the security side is needed, and separate cells deliver that news.

The Messenger Between Two Layers

There are cells in the body that travel back and forth between the security guards and the patrol. The Canadian-born immunologist Ralph Steinman was the first to discover these cells, known as dendritic cells (PMID 23681101). The 2011 Nobel Prize in Physiology or Medicine was awarded to Steinman, alongside Jules Hoffmann and Bruce Beutler, researchers who pioneered the field of innate immunity (PMID 23681101). This prize commemorated the immune role of Toll discovered in fruit flies, mammalian Toll-like receptors, and the fact that dendritic cells are the cells that initiate adaptive immunity (PMID 22539282).

Dendritic cells are immune cells that capture antigens throughout the body and present them to T cells. Dendritic cells capture antigens in tissues, process them, and display molecules on their surface that are necessary to wake up T cells. They then migrate to organs where immune cells gather, releasing cytokines to initiate an immune response (PMID 9521319).

Lymph nodes are small, bean-like organs located in the neck, armpits, groin, and elsewhere, where immune cells gather and meet one another. T cells that have not yet encountered anything cannot enter tissues. Therefore, dendritic cells must carry antigens from tissues all the way to the lymph nodes (PMID 37438021). They are messengers that tear off a piece of the intruder's face at the scene and run to the waiting room where the patrol waits.

What moves this messenger is the alarm of the security guards. When Toll-like receptors detect microbes, dendritic cells mature and their ability to present antigens increases. As a result, adaptive immunity is directed toward antigens originating from microbes (PMID 11861602). For this reason, Toll-like receptors are called the bridge that fills the empty space between innate immunity and adaptive immunity (PMID 35309296).

Dendritic cells work even when there is no inflammation. At those times, they present the body's own antigens or harmless external antigens, training T cells not to react to them (PMID 34859450, PMID 9521319). Why immunity does not attack its own body is explored in "Why Doesn't the Immune System Attack Us? — The Brakes on the Patrol".

Upon hearing the alarm, dendritic cells carry fragments of intruders to the lymph nodes, waking up adaptive immunity.

The Path a Single Splinter Took

We return to the first splinter. We line up what we saw earlier, one by one.

When a splinter pierces the skin, a gap opens in the first door. From the spot where the wall was breached, the immune system defends the body (PMID 39702433). At that site, there are substances released by injured cells, and if microbes came in on the splinter, their patterns are there too. Both are signals that trigger the guard's detection devices (PMID 31558839, PMID 11861602).

When the alarm sounds, immune cells in the blood gather at that spot following the concentration gradient created by cytokines (PMID 10719666). Amidst the same inflammation, dendritic cells at the site grab pieces of the microbe, mature, and leave for the lymph node (PMID 34859450).

In the lymph node, T cells that match those pieces wake up. Some grow to eliminate infected cells, while others grow to guide B cells in producing antibodies (PMID 34859450). When the fight ends, most of the T cells and B cells that worked against this opponent quickly vanish, and only some survive to become long-lived memory cells (PMID 9203411).

What can be said about this scene goes only as far as the sequence. How often this path goes all the way to the end from a single small wound is not told by the evidence gathered here.

The Next Meeting

Memory T cells make up the majority of the white blood cell group containing T cells and B cells for most of a person's life (PMID 24336101). Immune memory is when cells that recognize a previously encountered target survive for a long time, allowing a faster and more efficient response upon the next meeting. However, most of what we know about memory T cells comes from mouse studies. Mice do not replicate the human lifespan of encountering various disease-causing microbes over decades (PMID 24336101).

Some memory T cells do not circulate in the blood and instead remain in tissues. By definition, these cells can stay in tissues for months to years without antigen stimulation, blocking the same target closely and quickly when it returns. However, it is difficult to directly show whether these cells truly stay in one place (PMID 41985443).

Vaccines use this memory. A vaccine mimics the way the body encounters a disease-causing microbe, leaving memory in T cells and B cells before meeting the real target. The goal is to let the body counter the real target quickly and effectively later (PMID 30579659). Some components put into vaccines trigger guard sensors like Toll-like receptors to sound the alarm in place, which boosts the adaptive immune response. However, the exact way these components work is not yet fully uncovered (PMID 37468460).

Innate immunity was long described as an immune system without memory (PMID 30263032). Yet a phenomenon has been reported where innate immunity also becomes more resilient to recurrent infections, and this is seen in organisms lacking adaptive immunity as well as in mammals (PMID 27102489). Its mechanism differs greatly from adaptive memory in both the cells and the molecular pathways involved (PMID 40622547).

The patrol remembers encountered targets to block them faster next time, and vaccines leave that memory before you meet the real target.

When the Alarm Harms the Body

When the alarm system that fought infections turns on out of place, it can lead to shock that puts the whole body at risk. The same misalignment can actually weaken immunity, or cause immunity to attack its own body (PMID 20303872). When the mechanism that suppresses Tolllike receptor signals is released, or when this receptor recognizes the body's own molecules, it is strongly linked to inflammatory and autoimmune diseases (PMID 20404851).

An alarm that does not turn off is also a problem. Inflammation failing to subside on time is a core mechanism that worsens various diseases driven by inflammation (PMID 33915177).

Immune breakdowns come in two directions. On the side where responses weaken, there are immunodeficiency diseases where immunity fails to do its job (PMID 30263032). Examples of the side where responses are excessive or directed at the wrong target include autoimmune diseases, where immunity attacks its own tissues, and allergies, where immunity overreacts to substances that are harmless to most people (PMID 39702433). Allergies are continued in "What Is Allergy? — A False Alarm, and Why It Rings More Often".

The metaphors in this article have limitations. Guards and patrol squads have no headquarters issuing commands. Cells simply exchange signals like cytokines and move on the spot.

The alarm protects the body, but if it turns on out of place or fails to turn off on time, that alarm harms the body.

Where to Look Further

How dendritic cells, in the face of such diverse infections, properly awaken the T cells that lead the work of other immune cells is still only partly understood (PMID 32433540).

How far an infection in the respiratory tract spreads can be found in "How Do a Cold, the Flu, and Pneumonia Differ? — An Infection That Stays in the Entryway, and One That Reaches the Inner Room", and the story of how immunity keeps tuberculosis bacteria locked away for a long time can be found in "What Is Tuberculosis? — The Sleeping Ember, and the Fire That Takes Months to Put Out". Microbes living in the gut are covered by "What Do Gut Microbes Do? — Guests Who Eat the Leftovers, Guests Who Hold the Room".

The story of how the way vaccines leave behind memories led to medicines continues in "The Rejected Molecule — The Decades It Took for mRNA to Become Medicine", and how to tell apart events reported after a vaccine from things the vaccine actually caused is in "Between Reported and Caused — What Vaccine Safety Surveillance Caught, and What It Cleared".

The other pieces in this series follow one by one through the doors this article has opened. "What Is an Antibody? — Millions of Keys Cut in Advance, and the Ones That Fit" looks at how the body equips itself in advance with antibodies suited to an opponent it is seeing for the first time, and "Why Doesn't the Immune System Attack Us? — The Brakes on the Patrol" looks at why the immune system does not attack its own body. "What Is Allergy? — A False Alarm, and Why It Rings More Often" and "What Is Food Allergy? — Which Door Came First" deal with alarms ringing for harmless substances.

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