Variant TCR Ligands: New Insights into the Molecular Basis of Antigen-dependent Signal Transduction and T-cell Activation

Recent studies have identified peptide-MHC molecule ligands of alpha beta T-cell receptors with properties apparently distinct from classical agonists. These complexes, which are slight structural variants of the immunizing peptide or original presenting MHC molecule, have several novel properties. They can act as partial agonists able to induce only some and not other effector activities of the T cell, as antagonists able to inhibit T-cell functions stimulated by agonist ligand, or as mixed partial agonists/antagonists. Here we discuss the existing data suggesting that a simple receptor occupancy model does not account for the properties of these TCR ligands and review emerging data on qualitative differences in signal transduction following TCR engagement by priming versus variant complexes. We propose several non-exclusive models to explain both the biochemical and biological properties of variant ligands with partial agonist or antagonist properties