Thymus Physiology and T Cell Development
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Direct answer
The thymus deletes the overwhelming majority of the T cells it educates — well over 90% die within it — and that wastage is the price of self-tolerance. T cell progenitors from the bone marrow arrive through the corticomedullary junction and pass a two-gate examination: positive selection in the cortex, where thymocytes whose T cell receptors recognise self-MHC with adequate affinity survive (the rest die by neglect, and only MHC-restricted receptors pass), and negative selection in the medulla, where cells that recognise self-MHC plus self-peptide too strongly are deleted. The medullary epithelium expresses peripheral-tissue antigens — insulin, myelin proteins, retinal antigens — under the transcription factor AIRE, so the thymus previews the whole body to developing T cells; AIRE failure produces autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy with hypoparathyroidism, adrenal failure and mucocutaneous candidiasis. The thymus is largest relative to body size at birth (10-15 g, growing to 30-40 g at puberty) and then involutes into fat, yet continues exporting naive T cells into adult life at a declining rate.
What you must remember
- Selection gates: positive selection on cortical epithelial cells enforces MHC restriction; negative selection on medullary dendritic and epithelial cells deletes strong self-reactivity — over 90% of thymocytes die between them.
- Double-positive traffic: CD4-negative CD8-negative progenitors become double-positive cortex dwellers, then commit to CD4 (class II-restricted helper) or CD8 (class I-restricted cytotoxic) single-positive lineages before medullary export.
- AIRE and central tolerance: medullary epithelial cells express peripheral tissue antigens under the autoimmune regulator AIRE; its mutation causes APS-1/APECED, the named example of failed negative selection.
- Natural T regulatory cells: a minority whose receptors recognise self with intermediate affinity are groomed into CD4-positive, CD25-positive, FoxP3-positive suppressors — their IPEX-causing FoxP3 mutation shows what happens without them.
- Structure-function: cortex packed with immature thymocytes (dense on histology), medulla with mature cells, Hassall corpuscles as epithelial whorls; blood-thymus barrier protects developing cells from antigen exposure.
- Involution timeline: maximal relative size at birth, absolute peak around puberty, progressive fatty replacement thereafter — thymectomy in adults is immunologically tolerated, but childhood thymectomy impairs T cell diversity.
- Clinical anchors: DiGeorge syndrome (22q11 deletion, third-fourth pharyngeal pouch failure) with thymic aplasia, low T cells and normal immunoglobulins; myasthenia gravis with thymic hyperplasia or thymoma; and TREC-based newborn screening for severe combined immunodeficiency measuring thymic output.
A worked case: the DiGeorge newborn
An infant with low-set ears, a heart murmur and hypocalcaemic tetany on day two has an absent thymic shadow on chest radiograph. The embryology organises the physiology: the third and fourth pharyngeal pouches failed to form parathyroids (hence the hypocalcaemia), the thymic stroma (hence naïve T cell export fails) and the cardiac outflow apparatus (conotruncal defect) — the 22q11 deletion spectrum. Immunologically, T cells are low but immunoglobulin production is relatively preserved because B cells mature in marrow, not thymus: the inverse pattern of X-linked agammaglobulinaemia, and the discriminating answer when asked to place the lesion. In complete athymia, defence against fungi and viruses collapses and thymic transplantation or bone marrow transplantation follows; in partial forms, T cell numbers recover with age as the limited stroma suffices. The mirror image is the adult thymoma case: myasthenia gravis from antibodies against the nicotinic receptor, with the tumour generating the antigen-presenting milieu — removing it improves a proportion of patients, the clinical proof that this organ's physiology never stops mattering.
Where students slip
The two selections get swapped: cortical positive selection tests MHC restriction (survive if you can see self-MHC at all), medullary negative selection tests self-reactivity (die if you see it too well) — examiners award the mark for the direction of affinity, not the labels alone. Second, "thymus is vestigial after puberty" is false: output declines steeply but never stops, which is why adult thymectomy is tolerated while continuing to shrink the naive repertoire measurably. Third, students forget that T cells, unlike B cells, must be MHC-restricted — the entire reason positive selection exists, and the reason a thymus-educated cell rejects foreign MHC (transplant rejection begins in thymic education). Finally, myasthenia is linked to the thymus only vaguely in most answers; specify thymic hyperplasia in younger patients and thymoma in older ones, and add that the autoimmunity theory involves faulty AIRE-type presentation — a viva distinction worth a mark.
Frequently asked questions
What happens in positive and negative thymic selection?
Positive selection in the cortex retains thymocytes whose receptors recognise self-MHC with usable affinity; negative selection in the medulla deletes those that bind self-peptide-MHC too strongly.
What is the function of AIRE in the thymus?
It drives medullary epithelial cells to express peripheral tissue antigens for negative selection; its mutation causes autoimmune polyendocrinopathy with hypoparathyroidism, adrenal failure and candidiasis.
Which immunodeficiency results from thymic aplasia?
DiGeorge syndrome from 22q11 deletion — T cell lymphopenia with preserved immunoglobulins, plus hypocalcaemia and conotruncal heart disease.
Does the thymus function in adults?
Yes, at a declining rate — involution replaces much of it with fat, but naive T cell export continues lifelong, so adult thymectomy measurably narrows T cell receptor diversity.
Which clinical test reflects thymic output in newborns?
T cell receptor excision circle (TREC) assay on dried blood spots, used in newborn screening for severe combined immunodeficiency.