RESUMEN
Major Histocompatibility Complex (MHC) I and II and the αß T-cell antigen receptor (TCRαß) govern fundamental traits of adaptive immunity. They form a membrane-borne ligand-receptor system weighing host proteome integrity to detect contamination by nonself proteins. MHC-I and -II exhibit the "MHC-fold", which is able to bind a large assortment of short peptides as proxies for self and nonself proteins. The ensuing varying surfaces are mandatory ligands for Ig-like TCRαß highly mutable binding sites. Conserved molecular signatures guide TCRαß ligand binding sites to focus on the MHC-fold (MHC-restriction) while leaving many opportunities for its most hypervariable determinants to contact the peptide. This riveting molecular strategy affords many options for binding energy compatible with specific recognition and signalling aimed to eradicated microbial pathogens and cancer cells. While the molecular foundations of αß T-cell adaptive immunity are largely understood, uncertainty persists on how peptide-MHC binding induces the TCRαß signals that instruct cell-fate decisions. Solving this mystery is another milestone for understanding αß T-cells' self/nonself discrimination. Recent developments revealing the innermost links between TCRαß structural dynamics and signalling modality should help dissipate this long-sought-after enigma.