(284g) Antigen Quality Regulates Signaling and Degradation in the Immunological Synapse

Using in vitro and in silico approaches, we assessed the relationships between TCR signaling, synapse formation, TCR downregulation, and antigen quality. We found that a peptide that exhibits many hallmarks of a weak agonist (shorter half-life than the wild-type ligand, poor receptor downregulation, decreased p23 to p21 phospho-ζ ratio, and inefficient cSMAC formation) could stimulate T cells to proliferate more than the wild-type agonist ligand. Results from a computational model suggested that this is because the immunological synapse regulates the kinetics of signaling differently as antigen quality is varied. Although, in general, TCR signaling decreases for a ligand that binds TCR with a shorter half-life, our data suggest that in some cases, the inability to induce cSMAC formation can enhance the ability of some peptides to signal by attenuating TCR downregulation. We also describe how other parameters (e.g., the on-rate) influences signaling in the immunological synapse.