Thymic T-Cell Development & Central Tolerance
A thymocyte is not selected for what it recognises. It is selected for how strongly it recognises. That single idea explains the whole organ. Too weak a signal and the cell dies by neglect, which is the fate of roughly ninety per cent of them; too strong and it is deleted; and the narrow band in between is what leaves as a mature T cell. The same ligand, the same receptor and the same co-stimulation produce survival, death or a regulatory cell depending only on signal strength \u2014 which is why Nur77, CD5 and BIM matter more here than any individual antigen. The cortex tests on a peptide repertoire that exists nowhere else in the body; the medulla then shows the cell the rest of the body before it is allowed out. Click any protein for the matching Assay Genie ELISA kit or In Vivo antibody.
Affinity, not identity, decides. This is the one idea the whole organ runs on, and it is counter-intuitive enough that it is worth stating flatly: the thymus does not ask a thymocyte what it binds, it asks how hard. A TCR that binds self-peptide-MHC too weakly gets no survival signal and dies by neglect \u2014 the fate of the overwhelming majority. One that binds too strongly is deleted. The narrow window between those two thresholds is what becomes a T cell. CD5 and Nur77 are on this map because they are the only honest readouts of that quantity: both scale with the strength of the signal received, regardless of which ligand delivered it. A Nur77-GFP reporter is what made the model visible, and it remains the cleanest way to ask whether a thymocyte's problem is its receptor or its environment.
The cortex selects on a repertoire that exists nowhere else. Cortical epithelium runs \u03b25t, a proteasome subunit found in no other cell type, and cathepsin L in place of the usual class II editing enzymes. Both generate peptides that a peripheral cell cannot reproduce. This is not a quirk: it means positive selection deliberately tests against a shadow repertoire, so that a cell selected in the cortex is not thereby guaranteed to be activated by the same tissue outside. THEMIS is what makes the low-affinity reading possible at all, damping the signal just enough that a weak interaction registers as survival rather than as nothing. Lineage choice follows from which MHC class the receptor could engage \u2014 CD8 for class I, CD4 for class II \u2014 so the co-receptor a cell keeps is a record of how it was selected.
The medulla is where the body is shown to the immune system. CCR7 is switched on by positive selection and physically drags the survivor from cortex to medulla, so only cells that passed the first test ever sit the second. There AIRE forces medullary epithelium to transcribe insulin, thyroglobulin, myelin basic protein \u2014 tissue-restricted genes in the wrong tissue \u2014 and XCL1 recruits dendritic cells to cross-present what those rare cells made. The consequence of losing this is not a subtle immune defect but APECED, a multi-organ autoimmune disease. Note the inversion at CD80 and CD86: in the periphery, co-stimulation rescues a T cell; here it kills it. And BIM is the gene that proves the mechanism is apoptosis rather than anergy \u2014 delete it and self-reactive clones walk out into the periphery.
The third fate is the commercially interesting one. A thymocyte receiving an intermediate signal \u2014 too strong for simple survival, not quite strong enough to delete \u2014 can be diverted into FOXP3 instead of killed, and leaves as a regulatory T cell already carrying CTLA-4. This needs CD28 and it needs IL-2 that the cell does not make itself, which makes Treg development competitive and the niche small. The In Vivo tie-in, stated plainly: 14 of the 39 nodes carry a functional-grade antibody, and unusually they are spread across every stage rather than clustered \u2014 CD3\u03b5, CD4, CD8, CD25, CD44, CD24, CD127, MHC class I, CD40, CD86, IL-2, CTLA-4, TGF-\u03b2 and CD62L. The intracellular machinery is measurable rather than blockable. One practical warning: LPS causes acute thymic atrophy by itself, so endotoxin grade is not a nicety on this pathway \u2014 a contaminated antibody will shrink the organ you are trying to study. For research use only; not for use in diagnostic or therapeutic procedures.
Every protein node links to a product — ELISA kit, In Vivo antibody or research antibody.