How T cells discriminate foreign from self antigens
In plain words
Immune T cells must react to a few foreign protein fragments among many thousands of similar self fragments that bind only slightly less tightly. Simple proofreading cannot achieve both this sensitivity and this selectivity, so the actual mechanism is unknown.
Precise statement
T cells respond to approximately 1 to 10 agonist peptide-MHC ligands among approximately $10^{4}$ to $10^{5}$ self ligands whose receptor-binding lifetimes differ by a factor of order 3 to 10 (approximate). Kinetic proofreading of the McKeithan type trades sensitivity for specificity; identify the signaling mechanism (adaptive sorting, negative feedback, receptor clustering, force-dependent catch bonds) that achieves both, and test its predicted dose-response curves against data.
What would settle it
Dose-response measurements with ligands of controlled lifetime and density that match one model's predictions and exclude the alternatives.
Status in the literature
Unverified note
Adaptive-sorting network models and force-dependent binding remain competing explanations as of 2026, to this survey's knowledge.