The same molecule is the thing a T cell must recognise and the thing it must not recognise too well. That cannot be done with a filter. The thymus builds a window, and two per cent of cells fit through it.
The stub this page replaces was titled Jan Klein, while the Book VII index card cited Ludger Klein et al., 2014, Nature Reviews Immunology. Those are two different immunologists. Jan Klein (1936–) worked on the evolution of the MHC and trans-species polymorphism. Ludger Klein, in Munich, wrote the 2014 review on thymic selection that the index card names. The index card was right and the stub's title was wrong, and this chapter is Ludger Klein's. CITED
The thymus has a problem with no obvious solution. It must produce T cells that recognise foreign peptide presented on self MHC — so the receptor has to bind self-MHC, or it will never see anything. But a receptor that binds self-MHC bearing self-peptide too well is an autoimmune disease waiting to happen.
The same molecule is the thing you must recognise and the thing you must not recognise too well. There is no way to satisfy that with a filter. It needs a window.Which is what the thymus builds. A developing thymocyte carrying a randomly assembled receptor meets self-peptide–MHC on cortical epithelium and is read twice:
binds below lo → death by neglect — never receives a survival signal
binds between → positive selection — matures, leaves
binds above hi → negative selection — deleted, or diverted to a regulatory fate
Roughly two per cent of thymocytes complete the passage. The rest die in place, and the great majority of those die of the first threshold rather than the second — neglect, not deletion. CITED
That figure has usually been read as selection is stringent. It is worth reading instead as a statement about the geometry: the survivors are the mass of a distribution between two cuts, and two per cent is what tells you how far apart the cuts are.
Take receptor avidity for self-pMHC as a standardised log-scale variable. Then the surviving fraction is just the mass between the thresholds, and two per cent pins the window:
window [1.00, 1.50] → 9.19 %
window [1.00, 1.30] → 6.17 %
window [1.20, 1.45] → 4.15 %
window [1.00, 1.086] → 2.01 % COMPUTED
upper threshold −0.10 sd → 0.03 % survive — 67× fewer
upper threshold −0.05 sd → 0.87 % — 0.43×
baseline → 2.01 %
upper threshold +0.05 sd → 3.07 % — 1.5×
upper threshold +0.10 sd → 4.09 % — 2.0×
COMPUTED
A tenth of a standard deviation in one direction and the repertoire collapses; a tenth in the other and twice as many cells escape, carrying receptors that were supposed to be deleted. Immunodeficiency and autoimmunity are not opposite ends of a long scale. They are two sides of one cut, and the distance between them is small.
The rest of the mechanism is about making the cut in the right place, and the solution is the part of this biology most worth a corpus's attention.
A thymocyte in the cortex only ever meets peptides that the thymus happens to express. A receptor specific for insulin, or for a retinal protein, would never be tested — those proteins are not in the thymus. So medullary thymic epithelial cells express them anyway: driven by AIRE, and by Fezf2, they transcribe thousands of tissue-restricted genes in a promiscuous, cell-by-cell mosaic, so that a developing T cell walking through the medulla is shown pieces of organs it will never visit.
The threshold is useless unless the test set covers the space. The thymus does not make the cut sharper — it enlarges what is on the other side of it, by manufacturing a representation of the whole body inside one organ.
Mutations in AIRE give APECED, an autoimmune syndrome attacking several endocrine organs at once. The test set has holes, and the holes are the disease. CITED
The dm³ reading is direct, and the index card for this chapter had it: three stages, survival then positive then negative, are C, K, F — a constraint applied, a quantity driven toward a threshold, and a branch taken at it. What this page adds is that the fold here is two-sided, and that the corpus's usual picture — one threshold, cross it or do not — is the special case. A cell can fail by not reaching the fold at all.
Where this entered the teaching literature, which is the test of whether a finding has become knowledge rather than a result:
| Text | Where |
|---|---|
| Janeway’s Immunobiology, Murphy & Weaver | Thymic selection and central tolerance — mTEC promiscuous gene expression, AIRE, and the positive/negative selection of the T-cell repertoire |
| Kuby Immunology, Punt et al. | T-cell development and selection in the thymus, Ch. 8 |
| Annual Review of Immunology | Klein et al., antigen presentation and selection in the thymus |
“Klein-thymus” names a laboratory, not a book. There is no textbook by that title; what there is, is a body of papers out of Ludger Klein’s group in Munich and the reviews that consolidated them. The 2014 Nature Reviews Immunology review is open access at PMC4757912; the textbook chapters below are where it has been synthesised for teaching, and are the faster route in for a reader who is not an immunologist.
| Operator | In this chapter | In dm³ |
|---|---|---|
| C | a randomly assembled receptor meeting self-pMHC — the test applied | compression: the constraint |
| K | avidity, read against the lower threshold | the quantity driven toward $\kappa^*$ |
| F | two thresholds, not one — below is neglect, above is deletion | a two-sided fold SHOWN |
| U | the 2% that leave, and the regulatory lineage diverted rather than killed | the branches COMPUTED |
Every number on this page is produced by book7/ch-klein-thymus-verify.py. It records in its own closing block what it establishes and what it does not.
L. Klein, B. Kyewski, P. M. Allen and K. A. Hogquist, “Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see)”, Nat. Rev. Immunol. 14, 2014, 377–391. · doi 10.1038/nri3667 · PMID 24830344 · open access at PMC4757912.
B. Kyewski and L. Klein, “A central role for central tolerance”, Annu. Rev. Immunol. 24, 2006.
M. S. Anderson et al., “Projection of an immunological self shadow within the thymus by the Aire protein”, Science 298, 2002.
T. Takaba et al., “Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance”, Cell 163, 2015.
K. A. Hogquist and S. C. Jameson, “The self-obsession of T cells”, Nat. Immunol. 15, 2014.
K. Murphy and C. Weaver, Janeway’s Immunobiology, 10th ed., Garland — thymic selection and central tolerance.
J. Punt et al., Kuby Immunology, 8th ed., Macmillan — Ch. 8, T-cell development and selection in the thymus.