Central vs peripheral tolerance: how lymphocytes learn self-tolerance
Receptors are built at random, so some will recognise the body's own molecules. Central tolerance removes them in the thymus and bone marrow; peripheral tolerance catches those that slip through.
Explain central tolerance (thymic positive and negative selection, AIRE) and peripheral tolerance (anergy, regulatory T cells, Fas–Fas ligand apoptosis), and name the disease that follows failure of each (APECED, IPEX, ALPS).
The short version
- Central tolerance removes self-reactive cells in the thymus (T cells, helped by AIRE) and the bone marrow (B cells, by receptor editing, deletion or anergy).
- Positive selection in the cortex removes T cells that cannot recognise self MHC; negative selection in the medulla removes T cells that bind self peptide too strongly.
- Peripheral tolerance is anergy, regulatory T cells and Fas–Fas ligand apoptosis.
- AIRE fails in APECED, FOXP3 in IPEX and Fas in ALPS.
Why central vs peripheral tolerance exists
A nine-year-old girl has thrush again and again. Her parathyroid glands have failed, so her calcium is low, and her adrenal glands are failing too. One gene, several glands, all attacked by her own immune system. How?
The answer is central vs peripheral tolerance. T and B cell receptors are built by random gene rearrangement, so some will recognise the body's own molecules. Tolerance removes or silences those cells.[1][2]
Central tolerance happens in the primary lymphoid organs, mainly by negative selection: the thymus for T cells and the bone marrow for B cells. Peripheral tolerance happens afterwards, in the tissues, for cells that slipped through.[2][9]
Thymic selection: positive and negative selection
Start in the thymic cortex. Epithelial cells there show developing T cells self peptides on MHC. A T cell that cannot recognise self MHC gets no survival signal and dies: death by neglect. That is positive selection.[1][9]
The survivors move to the medulla. If a T cell binds self peptide too strongly, it is told to undergo apoptosis. That is negative selection, or clonal deletion.[1][9]
| Step | Where | What happens |
|---|---|---|
| Positive selection | Thymic cortex | A T cell that cannot recognise self MHC gets no survival signal and dies (death by neglect) |
| Negative selection | Thymic medulla | A T cell that binds self peptide too strongly undergoes apoptosis (clonal deletion) |
AIRE: showing the body's proteins in the thymus
Negative selection has a limit, and AIRE is how the thymus works around it.
The medulla can only delete what it can show. Medullary epithelial cells use the transcription factor AIRE, the autoimmune regulator, to switch on genes for other organs' proteins, such as insulin.[2][3][9]
So T cells that would attack the pancreas or the adrenal gland meet their targets in the thymus, and are removed.[2][9]
Lose AIRE, and negative selection fails for those organ proteins. That is APECED, autoimmune polyendocrine syndrome type 1 (APS-1), with failing endocrine glands and chronic candidiasis. It is not X-linked. That is the girl from the opening.[2][3]
Peripheral tolerance: anergy, regulatory T cells and Fas
Peripheral tolerance has three main backups for cells that escaped the thymus.[2][9]
- AnergyA T cell that sees its antigen (signal one) without co-stimulation through CD28 and B7 (signal two) becomes unresponsive.[6][9]
- Regulatory T cellsMarked by CD4, CD25 and the transcription factor FOXP3. They suppress other T cells, partly through IL-10 and TGF-β.[3][5]
- Fas and Fas ligandFas on an activated lymphocyte, engaged by Fas ligand, triggers its apoptosis.[8]
Anergy is why signal one alone is not enough: without signal two, the cell is switched off rather than activated. Regulatory T cells and Fas work differently: one suppresses other T cells, the other triggers the death of activated lymphocytes.[3][5][6][8]
All three are peripheral, so all three act after a cell has left the thymus or bone marrow.[2][9]
When tolerance fails: APECED, IPEX and ALPS
Lose FOXP3 and you lose regulatory T cells. That is IPEX, an X-linked disease, mostly in boys, with autoimmune enteropathy, early diabetes and eczema.[3][4]
Lose Fas, and lymphocytes pile up. That is ALPS, autoimmune lymphoproliferative syndrome, with big lymph nodes, a big spleen and autoimmune low blood counts.[2][3]
| Gene | Checkpoint that fails | Disease | Key features |
|---|---|---|---|
| AIRE | Negative selection of T cells against organ proteins (central) | APECED (APS-1) | Failing endocrine glands, chronic candidiasis; not X-linked |
| FOXP3 | Regulatory T cells (peripheral) | IPEX | X-linked, mostly boys; autoimmune enteropathy, early diabetes, eczema |
| Fas | Apoptosis of activated lymphocytes (peripheral) | ALPS | Big lymph nodes, big spleen, autoimmune low blood counts |
Three things to keep
- Central tolerance deletes self-reactive cells in the thymus, helped by AIRE.
- Peripheral tolerance is anergy, regulatory T cells and Fas.
- AIRE fails in APECED, FOXP3 in IPEX, and Fas in ALPS.
Practice question
Original · USMLE styleA 5-month-old boy is brought to the emergency department with 3 weeks of watery diarrhoea, poor weight gain and an eczematous rash. His plasma glucose is 410 mg/dL and islet autoantibodies are present. His lymph nodes and spleen are not enlarged. His mother's brother died in infancy of a similar illness.
Common questions
What is the difference between central and peripheral tolerance?
Central tolerance happens in the primary lymphoid organs: the thymus for T cells and the bone marrow for B cells. Peripheral tolerance happens afterwards, in the tissues, for cells that slipped through.
What is the difference between positive and negative selection?
Positive selection happens in the thymic cortex: a T cell that cannot recognise self MHC gets no survival signal and dies (death by neglect). Negative selection happens in the medulla: a T cell that binds self peptide too strongly undergoes apoptosis.
What does AIRE do?
AIRE is a transcription factor in medullary thymic epithelial cells that switches on genes for other organs' proteins, such as insulin, so that T cells that would attack those organs are removed. Loss of AIRE causes APECED.
What are the mechanisms of peripheral tolerance?
Anergy, regulatory T cells and Fas–Fas ligand apoptosis. Their failures are linked to IPEX (FOXP3, regulatory T cells) and ALPS (Fas).
Transcript
Read the full narration, by chapter672 words
0:00The case: thrush, low calcium and failing adrenals
A 9-year-old girl has had thrush in her mouth again and again. Now her parathyroid glands have failed, so her calcium is low, and her adrenals are failing too. One gene, several glands, all attacked by her own immune system. How? Today: how lymphocytes learn not to attack
0:17Today: how lymphocytes learn not to attack the body
the body, and what breaks when it fails. Lymphocyte receptors are built by random gene rearrangement, so some will recognise the body's own molecules, and tolerance removes or silences those cells. Central tolerance happens in the primary lymphoid organs: the thymus for T cells, the bone marrow for B cells. Peripheral tolerance happens afterwards, in the tissues, for cells that slipped through.
0:46Thymic cortex: positive selection and death by neglect
Start in the thymic cortex. Epithelial cells there show developing T cells self peptides on MHC. AT cell that cannot recognise self MHC gets no survival signal and dies: death by neglect. That is positive selection.
1:04Thymic medulla: negative selection (clonal deletion)
The survivors move to the medulla. If a T cell binds self peptide too strongly, it is told to undergo apoptosis. That is negative selection, or clonal deletion.
1:16AIRE: showing the body's proteins in the thymus
But the medulla can only delete what it can show. Medullary epithelial cells use the transcription factor Air-ee, the autoimmune regulator, to switch on genes for other organs' proteins, such as insulin. So T cells that would attack the pancreas or the adrenal gland meet their targets in the thymus, and are removed. Lose Air-ee, and negative selection fails
1:39When AIRE fails: APECED (APS-1)
for those organ proteins: that is APECED, autoimmune polyendocrine syndrome type one, with failing endocrine glands and chronic candidiasis. That is our girl. B cells have their own central checkpoint,
1:55B-cell central tolerance in the bone marrow
in the bone marrow. AB cell that binds self can edit its receptor, be deleted, or be made anergic.
2:05Peripheral backup 1: anergy
Now the peripheral backups. There are three. One: anergy. AT cell that sees its antigen, signal one, without co-stimulation through CD28 and B7, signal two, becomes unresponsive.
2:22Peripheral backup 2: regulatory T cells, FOXP3 and IPEX
Two: regulatory T cells, marked by CD4, CD25 and the transcription factor fox P three. They suppress other T cells, partly through IL 10 and TGF beta. Lose fox P three and you lose regulatory T cells: IPEX, an X-linked disease, mostly in boys, with autoimmune enteropathy, early diabetes and eczema. Three: Fas and Fas ligand.
2:49Peripheral backup 3: FAS-FAS ligand and ALPS
Fas on an activated lymphocyte, engaged by Fas ligand, triggers its apoptosis. Lose Fas, and lymphocytes pile up: autoimmune lymphoproliferative syndrome, with big lymph nodes, a big spleen and autoimmune low blood counts. Your turn.
3:09Practice question
A five-month-old boy has three weeks of watery diarrhoea, poor weight gain and an eczematous rash. His plasma glucose is 410 milligrams per decilitre, and islet autoantibodies are present. His lymph nodes and spleen are not enlarged. His mother's brother died in infancy of a similar illness. Which of the following is the most likely underlying defect? A, failure of negative selection of T cells, due to a mutation in Air-ee. B, failure of regulatory T cell function, due to a mutation in fox P three. C, failure of apoptosis of activated lymphocytes, due to a mutation in Fas. D, failure of positive selection of T cells, due to absent MHC on thymic cortical epithelium. E, failure of T cell anergy, due to absent CD28 on T cells. Pause here and decide.
4:12The wrong options first, struck one by one
A is out: Air-ee loss gives endocrine failure and candidiasis, and is not X-linked. C is out: Fas defects give big nodes and a big spleen, which he does not have. D is out: failed positive selection leaves too few mature T cells, so immunodeficiency, not autoimmunity. E is out: without CD28, T cells get less co-stimulation, which favours anergy rather than losing it. The answer is B.
4:42The answer: FOXP3 and IPEX
Diarrhoea, early diabetes and eczema in an infant boy with an affected maternal uncle is IPEX: no fox P three, no regulatory T cells.
4:57Recap and next lesson: the complement system
Three things to keep. One: central tolerance deletes self-reactive cells in the thymus, helped by Air-ee. Two: peripheral tolerance is anergy, regulatory T cells and Fas. Three: Air-ee fails in APECED, fox P three in IPEX, and Fas in ALPS. Next, the complement system and its three pathways.
Sources
Numbers in the text, e.g. [1], point here- The partitioning of TCR repertoires by thymic selection. J Exp Med. 2024. europepmc.org/article/PMC/PMC11338286
- Genetic basis of defects in immune tolerance underlying the development of autoimmunity. Front Immunol. 2022. europepmc.org/article/PMC/PMC9376219
- International Union of Immunological Societies Expert Committee classification of primary immunodeficiencies, 2017 (APECED, IPEX and ALPS entries). europepmc.org/article/PMC/PMC5742601
- Loss of Foxp3 and autoimmunity (X-linked IPEX). Front Immunol. 2023. europepmc.org/article/PMC/PMC10183596
- Regulatory T cell review (CD25+CD4+ FOXP3 Tregs; IL-10, TGF-beta, IL-35). 2026. europepmc.org/article/PMC/PMC13691435
- T cell anergy and absent costimulation (Cbl-b). 2021. europepmc.org/article/PMC/PMC8117209
- B-cell tolerance review (receptor editing, clonal deletion, anergy). 2026. europepmc.org/article/PMC/PMC13743777
- FAS-mediated apoptosis and activation-induced cell death (c-FLIP review). 2026. europepmc.org/article/PMC/PMC13233873
- Wikipedia: Central tolerance; Peripheral tolerance (secondary source, opened 13 Nov 2026). en.wikipedia.org/wiki/Central_tolerance · en.wikipedia.org/wiki/Peripheral_tolerance
The patient in the opening case is a teaching vignette and no calcium value is shown.
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (cropped, recoloured, outlined): child, baby, Candida albicans, thymus, kidney with adrenal gland, pancreatic islet, intestine, skin, spleen. NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain, adapted (recoloured, outlined): bone marrow, lymph node, T cell, apoptosis, B-cell receptor, dendritic cell, MHC class II-CD4-TCR complex, complement C1 complex. Parathyroid glands: Gray's Anatomy plate 1177 (Henry Vandyke Carter) via Wikimedia Commons, public domain. The thymus lobule, cells, receptors, AIRE schematic, signal diagrams, lab slip, question card, pocket card and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-IMM-006.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01MHC I vs MHC II: how antigen presentation works5:03
- EP 02T-cell activation: the two-signal model4:58
- EP 03Th1, Th2, Th17 and Treg: helper T-cell subsets5:13
- EP 04Antibody isotypes and class switching5:13
- EP 05Central vs peripheral tolerance: how lymphocytes learn self-tolerance5:26
- EP 06Complement system explained: three pathways, one ending5:24
- EP 07Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor5:15
- EP 08Hypersensitivity types I to IV: the four effectors5:20
- EP 09B-cell vs T-cell immunodeficiency: predict the infections5:24
- EP 10Hyper IgM syndrome: CD40 ligand and class switching5:19
- EP 11Chronic granulomatous disease: NADPH oxidase and the respiratory burst5:20
- EP 12Leukocyte adhesion deficiency: CD18 and neutrophil extravasation5:01
- EP 13Transplant rejection explained: hyperacute, acute, chronic and GVHD5:51
- EP 14Vaccine types explained: live, inactivated, conjugate and mRNA5:41