Your immune system has two layers, and the 2025 Nobel went to its brakes

Key takeaways

• The 2025 Nobel Prize in Physiology or Medicine went to Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi for discovering how regulatory T cells keep the immune system from attacking the body¹².
• Your innate layer, which includes skin, mucus, stomach acid, fast white cells and blood proteins, acts first but doesn’t learn; the adaptive layer learns a specific germ but needs about 4 to 7 days the first time⁵⁷.
• Adaptive cells don’t fully switch on without a signal from the innate layer, which is why some vaccines carry an adjuvant to sound that alarm⁸¹¹.
• When the balance tips, the result can be allergy, which affects roughly 20% to 30% of people, autoimmune disease, or immune deficiency, which has more than 550 rare inherited forms⁶¹³.
• Infections that keep coming back, are unusually severe or respond poorly to treatment can signal an immune problem worth raising with a clinician¹⁵.

On October 6, 2025, Mary Brunkow’s phone showed a call from a Swedish number. The Seattle scientist, then 64, figured it was spam and ignored it¹.

She got the news from an Associated Press photographer who came to her home early that morning¹. She had won the Nobel Prize in Physiology or Medicine, shared with Fred Ramsdell of San Francisco and Shimon Sakaguchi of Osaka University in Japan¹².

The prize honored work on “peripheral immune tolerance,” the system that keeps your defenses from attacking your own organs¹. The Nobel Foundation called the cells at its center, regulatory T cells, the immune system‘s “security guards”¹.

Guards matter because your immune system isn’t a single force. It works in two layers. One is ancient and fast and ready at birth. The other is newer and slower, and it learns.

Each layer needs the other, and both need brakes. This guide covers how they work together and what happens when the balance tips.

The first layer is ancient, fast and needs no training

Scientists call the inborn layer innate immunity. It is very old. A standard immunology textbook traces it back to single-celled life such as the amoeba⁴.

Its outer wall is physical. MedlinePlus, the National Library of Medicine’s health site, lists your skin, germ-trapping mucus, the cough reflex, stomach acid, and germ-fighting enzymes in your tears and skin oil⁵.

Germs that get past the wall meet fast white blood cells. Neutrophils make up more than half the white cells in your blood, and they mainly fight bacteria and fungi, says the Immune Deficiency Foundation, a patient group⁶. Other cells, called phagocytes, swallow germs and dead tissue. Pus is largely their remains⁵.

Natural killer cells, or NK cells, destroy cells that viruses have taken over⁶. Complement, a set of about 30 blood proteins mostly made in the liver, coats bacteria so they’re easier to eat. Some of its proteins can also break open bacterial walls⁶.

The innate layer sends chemical alarms, too. One of them, interleukin-1, causes fever⁵.

None of this takes practice. Innate cells react quickly and broadly to signs of danger, and the reaction usually shows up as inflammation⁸. The trade-off is that innate responses don’t build a lasting memory of a specific germ⁷.

How do untrained cells spot a germ? Part of the answer came from fruit flies and won half of the 2011 Nobel Prize⁹. In 1996, Jules Hoffmann’s team in France found that flies need a gene called Toll to fight fungi and some bacteria⁹.

In 1998, Bruce Beutler found a similar sensor that detects a bacterial molecule called LPS. It’s now named Toll-like receptor 4, and more than nine others have turned up since⁴⁹. The National Institute of Allergy and Infectious Diseases (NIAID) says these sensors pick up broad danger signals shared by viruses, bacteria and fungi, but can’t tell one strain from another⁸.

The second layer learns, and its first lesson takes days

The learning layer is called adaptive immunity. In evolution it shows up suddenly, in the cartilaginous fish, the group that includes sharks⁴.

Its main players are lymphocytes, white cells that come in two kinds. B cells grow into plasma cells that make antibodies, proteins that grab one specific target so other cells can destroy it⁵. T cells attack infected cells directly and help steer the rest of the response⁵.

T cells split the work. Killer T cells destroy cells infected with viruses. Helper T cells help B cells make antibodies and support the killers. Regulatory T cells tell the others when to stand down⁶.

How can this layer recognize a germ it has never met? As lymphocytes mature, they shuffle their receptor genes at random⁸. As a result, your body carries lymphocytes aimed at at least 100 million different targets at any one time⁷. Cells that react to your own tissues are supposed to be weeded out⁸.

The catch is time. When a lymphocyte meets its match, it divides two to four times a day for three to five days, building a clone of about 1,000 identical cells⁷. That’s why a first adaptive response takes about 4 to 7 days to kick in, and the innate layer has to hold the line until then⁷.

The payoff is memory. A second meeting with the same germ brings a faster, bigger response⁷. Our companion article on immune memory explains how long it lasts.

Dendritic cells carry the message between the layers

The two layers aren’t separate armies. The bridge between them is a cell that Ralph Steinman of Rockefeller University described in 1973, the dendritic cell⁹.

A dendritic cell picks up a germ in infected tissue, becomes activated and travels to a nearby lymph node⁷. NIAID calls lymph nodes a communication hub, where immune cells sample what’s coming in from the rest of the body¹⁰.

In the node, the dendritic cell shows germ fragments to T cells. Spotting a fragment isn’t enough. A T cell also needs a second signal, which the activated dendritic cell supplies⁷. NIAID calls this a system of checks and balances that helps prevent needless attacks on the body⁸.

Steinman shared the 2011 prize but never knew it. He died of pancreatic cancer a few days before the announcement, and the Nobel Assembly kept the award despite its rule against honoring people after death⁹.

Why some vaccines carry an extra ingredient

The two-layer design explains a vaccine ingredient some readers worry about: adjuvants. A vaccine’s goal is to teach the adaptive layer. But NIAID says an effective vaccine must switch on both layers, because the adaptive layer can’t reach its full strength without an innate response⁸. Adjuvants are added to ring that innate alarm⁸.

CDC explains why this matters more today. Many modern vaccines contain only small pieces of a germ, such as proteins, and those pieces often need help to trigger a strong enough response¹¹. Aluminum salts were first added to diphtheria and tetanus vaccines in the 1930s through 1950s and have been used for more than 70 years¹¹.

You may feel the result. CDC says adjuvanted vaccines can cause more sore arms, fever, chills and body aches than vaccines without one¹¹. That is the innate layer reacting as intended. Many vaccines, including MMR and the mRNA COVID-19 shots, contain no adjuvant at all¹¹.

CDC’s adjuvant page was last updated in December 2024¹¹. For who recommends which vaccines now, and why schedules now differ, see “How to read competing vaccine schedules now that the advice has split.”

The brakes: regulatory T cells were once a doubted idea

A defense this strong needs a way to stand down. That question drove Sakaguchi’s career.

His 1985 mouse experiments pointed the way. When he took away a subset of T cells from otherwise healthy animals, their immune systems turned on their own organs². For a while, The Lancet reports, discouraging results drove many immunologists to give up on so-called suppressor cells. Sakaguchi kept at it².

A decade later he pinned down the culprit. Roughly 1 in 10 helper-type T cells, called CD4 cells, also carried a surface marker called CD25. Mice lacking that slice developed autoimmune symptoms, which faded once the cells were restored. Sakaguchi gave the group its name: regulatory T cells².

Brunkow and Ramsdell came at the puzzle through genes, at a Seattle company called Darwin Molecular³. They studied scurfy mice, a strain bred at Oak Ridge National Laboratory during radiation research, whose immune systems run out of control²³. The fault lay on the X chromosome. After whittling the suspects to 20 genes, the pair traced the disease to a small mutation in one, now called FOXP3².

They published in 2001, alongside a report that mutations in the human version of the gene cause a rare disease called IPEX³. In 2003, three labs, including Ramsdell’s and Sakaguchi’s, showed that FOXP3 is essential for making regulatory T cells³.

These cells make up only about 1% to 2% of the T cells in blood and lymph tissue³. One way they calm a response is by soaking up IL-2, a growth signal other T cells need³.

IPEX shows what happens without them. MedlinePlus Genetics says it affects about 1 in 1.6 million people, mostly males. Severe diarrhea usually starts in the first months of life, often with type 1 diabetes and eczema, because the immune system can’t switch off responses it doesn’t need¹².

The work has led to more than 200 clinical trials². A 2025 commentary describes early tests in kidney transplants and rheumatoid arthritis and says the field is only beginning³. Its author, Jeffrey Bluestone, leads Sonoma Biotherapeutics, a company developing these treatments that Ramsdell also cofounded²³.

When the balance tips: allergy, autoimmunity and deficiency

Immune trouble comes in three main forms: a response aimed at something harmless, one aimed at you, and one that’s too weak⁵.

Allergy. Here the immune system treats something harmless as a threat. National Jewish Health explains that T cells flag the substance and B cells make IgE antibodies against it. That IgE settles on mast cells in the skin and airways and can stay there for years¹³.

On the next exposure, those cells release histamine, which makes blood vessels leaky and sets off itching¹⁴. Allergies affect roughly 20% to 30% of people, and most start in early childhood¹³. The severe form, anaphylaxis, can swell the airways and drop blood pressure fast. MedlinePlus says it can be fatal and must be treated with a shot of epinephrine¹⁴.

Autoimmunity. Here tolerance breaks, and the immune system attacks the body’s own tissue, as in rheumatoid arthritis⁵. Nobel committee chair Olle Kämpe said the Treg discoveries help explain why not everyone develops serious autoimmune disease¹. For how common these diseases are, see “Your immune system works more like a team than a volume knob, and some habits help it.”

Immune deficiency. Here part of a layer is missing or weak. The Immune Deficiency Foundation counts more than 550 rare inherited forms⁶. Newborn screening for one of the most severe, called SCID, measures tiny DNA circles that form as T cells mature⁶.

Deficiency can also be acquired. MedlinePlus lists HIV, malnutrition, many cancers, chemotherapy, corticosteroids and other drugs that weaken immunity, and removal of the spleen. It adds that the immune system becomes less effective with age¹⁵.

The immune system at a glance

Use this table as a map of who does what.

Team	Main players	How fast	What it remembers	Where you might notice it
Barriers (innate)	Skin, mucus, cough reflex, stomach acid, enzymes in tears and skin oil5	Always on	Nothing specific	A cough that clears an irritant from your airway5
Front-line cells (innate)	Neutrophils, phagocytes, NK cells, complement proteins56	Fast; they hold the line for the first days78	Little; some NK cells are an exception10	Pus in an infected cut, made largely of dead germs and white cells5
Alarm signals (innate)	Interleukin-1 and other chemical messengers5	Fast	Nothing	Fever early in an infection5
The bridge	Dendritic cells79	Carry germ pieces to lymph nodes and give T cells a second signal7	They start the learning but don’t store it	Why some vaccines include an adjuvant811
Antibody makers (adaptive)	B cells and plasma cells making IgM, IgG, IgA and IgE56	About 4 to 7 days the first time; faster later7	Yes, through memory cells5	Antibodies after an infection or a vaccine5
Hunters and helpers (adaptive)	Killer and helper T cells6	About 4 to 7 days the first time; faster later7	Yes, through memory cells5	Clearing cells that a virus has taken over6
Brakes (adaptive)	Regulatory T cells, about 1% to 2% of T cells3	Ongoing; they switch off responses that aren’t needed12	They maintain tolerance to your own tissues12	Missing in IPEX, a rare disease of runaway immune attack12

How strong is the evidence?

Claim	What the research shows	Evidence level
Immunity runs on an innate and an adaptive layer that depend on each other	Long-established textbook science; NIAID says the adaptive layer needs innate signals to work fully78	Strong evidence
Regulatory T cells keep the immune system from attacking the body	Remove-and-return experiments in mice, plus FOXP3 mutations causing IPEX in people2312	Strong evidence
Adjuvants strengthen vaccine responses	In use for more than 70 years; they also cause more sore arms and aches11	Strong evidence
Treatments built on regulatory T cells help transplant or autoimmune patients	More than 200 trials have started, most at early stages23	Promising but early
“Boosting” one immune layer makes a healthy person sick-proof	No good evidence; an overactive response is what drives allergy and autoimmune disease10	Not enough evidence

Balance, not a boost: what the two layers mean for you

Natural-health traditions often speak of balance and the body’s own wisdom. Immunology says something close in its own language. The system that protects you depends on restraint as much as on attack.

That’s why turning up one layer isn’t a sensible goal. A response that fires without a real threat, or won’t switch off, is what leads to allergy and autoimmune disease¹⁰. Our article on why the immune system isn’t a volume knob reviews the evidence on sleep, movement and supplements, and later articles ask whether immune “boosting” means anything at all.

Some support is basic. Malnutrition is one cause of acquired immune deficiency, and MedlinePlus notes that good nutrition may prevent that kind¹⁵.

Fever deserves respect, too. It’s one of the innate layer’s own tools⁵. Our companion article on inflammation and infection explains why it usually helps and when it needs care.

Vaccines work with this design, letting the adaptive layer learn without the infection itself⁵⁸. Whether to get a particular vaccine is a decision to make with a clinician you trust.

Questions readers ask

The bottom line

Your immune system works in two layers. The innate layer is old, fast and always ready, and the adaptive layer is slower but learns. Dendritic cells link them, and regulatory T cells, the subject of the 2025 Nobel, keep the whole system from turning on you.

Most immune trouble comes from balance gone wrong: too little response, too much, or a response aimed at the wrong target. The goal isn’t a louder immune system but a well-regulated one. Respect fever and inflammation as defenses, take frequent or severe infections seriously, and make vaccine choices with a clinician you trust.

Related reading

• Inflammation isn’t always infection, and sepsis is the infection that can’t wait
• Your immune system works more like a team than a volume knob, and some habits help it
• How to read competing vaccine schedules now that the advice has split
• Stress can reach your immune cells, but positive thinking still can’t cure cancer
• Inflammation can harm your heart, but an “anti-inflammatory” label proves little

Sources

1. Wade K. “Seattle Scientist Shares Nobel Prize in Medicine for Work on the Human Immune System” (citing Associated Press reporting). KIRO 7 News, October 6, 2025. kiro7.com
2. Burki T. “The Origins of Tolerance: The 2025 Nobel Prize in Medicine.” The Lancet, 2025;406:1714–1715 (copy hosted by the Institute for Systems Biology, Brunkow’s employer). isbscience.org
3. Bluestone JA. “The 2025 Nobel Prize in Physiology or Medicine — A Bridge to Peripheral Immune Tolerance.” Journal of Clinical Investigation, 2025;135(23):e202216. The author discloses that he is cofounder and CEO of Sonoma Biotherapeutics, a regulatory T-cell therapy company. doi.org
4. Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease, 5th ed. Garland Science, 2001. Contents and chapter summaries, including “Afterword: Evolution of the Immune System.” NCBI Bookshelf NBK10757. ncbi.nlm.nih.gov
5. MedlinePlus Medical Encyclopedia. “Immune Response.” National Library of Medicine, reviewed January 20, 2026. medlineplus.gov
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7. Janeway CA Jr, et al. “Principles of Innate and Adaptive Immunity.” Immunobiology, 5th ed. Garland Science, 2001. NCBI Bookshelf NBK27090. ncbi.nlm.nih.gov
8. National Institute of Allergy and Infectious Diseases. “Features of an Immune Response.” NIH, accessed October 2026. niaid.nih.gov
9. Nature Immunology (editorial). “Immunology in the Limelight.” Nature Immunology, 2011;12(12):1127. nature.com
10. National Institute of Allergy and Infectious Diseases. “Overview of the Immune System.” NIH, accessed October 2026. niaid.nih.gov
11. Centers for Disease Control and Prevention. “Adjuvants and Vaccines.” Vaccine Safety, first published August 13, 2024, last updated December 20, 2024. cdc.gov
12. MedlinePlus Genetics. “Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome.” National Library of Medicine, last updated May 1, 2017. medlineplus.gov
13. National Jewish Health. “Allergy: Causes.” Reviewed by Kanao Otsu, MD, MPH, July 31, 2026. nationaljewish.org
14. MedlinePlus. “Histamine: The Stuff Allergies Are Made Of” (video and transcript). National Library of Medicine, published September 8, 2017, updated April 1, 2019. medlineplus.gov
15. MedlinePlus Medical Encyclopedia. “Immunodeficiency Diseases.” National Library of Medicine, reviewed January 20, 2026. medlineplus.gov