T-cell virtuosity in ''knowing thyself"

Major Histocompatibility Complex (MHC) I and II and the alpha beta T-cell antigen receptor (TCR alpha beta) 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 TCR alpha beta highly mutable binding sites. Conserved molecular signatures guide TCR alpha beta 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 alpha beta T-cell adaptive immunity are largely understood, uncertainty persists on how peptide-MHC binding induces the TCR alpha beta signals that instruct cell-fate decisions. Solving this mystery is another milestone for understanding alpha beta T-cells' self/nonself discrimination. Recent developments revealing the innermost links between TCR alpha beta structural dynamics and signalling modality should help dissipate this long-sought-after enigma.