MODULATION OF NAIVE CD4 T-CELL ACTIVATION WITH ALTERED PEPTIDE LIGANDS - THE NATURE OF THE PEPTIDE AND PRESENTATION IN THE CONTEXT OF COSTIMULATION ARE CRITICAL FOR A SUSTAINED RESPONSE

Altered peptide ligands containing single amino acid substitutions hav e the potential to be used for modulating immune function, Using a pan el of moth cytochrome c peptides, we demonstrate that different phases of naive CD4 T cell response are alternately modulated depending on a ltered peptide ligand dose and accessory molecule expression by APC. W eak agonists presented at high concentration, and with costimulation, efficiently induced early phase naive T cell activation as assessed by IL-2R/CD69 expression, but could only promote sufficient IL-2 for a s hort-lived proliferative response, In contrast, strong agonists and he teroclitic peptides induced early phase T cell activation even at low concentrations with costimulation, and allowed sustained IL-2 secretio n and proliferation, In the absence of accessory molecule help, early and late phase activation was impaired with weak agonists, whereas str ong agonists partially compensated for a lack of costimulation for ear ly phase activation, and also promoted enhanced IL-2 with sustained pr oliferation, These studies support the hypothesis that the naive T cel l response will be determined by the balance between provision of acce ssory molecule help and the affinity of peptide/MHC complexes for indi vidual TCRs, and suggest that extended IL-2 production is the main fac et of naive CD4 activation that is affected by altering the nature of the peptide.