Altered Peptide Ligands Induce Delayed CD8-T Cell Receptor Interaction—a Role for CD8 in Distinguishing Antigen Quality

SummaryHow T cells translate T cell receptor (TCR) recognition of almost identical pMHC ligands into distinct biological responses has remained enigmatic. Although differences in affinity or off rate are important, they offer at best an incomplete explanation. By using Förster resonance energy transfer (FRET), we have visualized the ligand-induced interaction between OT-I TCR and CD8. We found that both recruitment of TCR to the immunological synapse and the TCR-CD8 interaction induced by weak agonists (positive-selecting ligands) was delayed but not necessarily weaker than strong agonists (negative selectors). A delayed and perhaps longer lasting CD8-TCR interaction results in delayed phospho-ERK recruitment to the synapse. The kinetics of the TCR-CD8 interaction can reconcile previously anomalous data, where biological activity did not correlate with TCR-pMHC binding kinetics for certain ligands. Our findings indicate that the T cell translates antigen recognition into T cell responses by differential recruitment of CD8 to the TCR.