INHIBITION OF TCR TRIGGERING BY A SPECTRUM OF ALTERED PEPTIDE LIGANDSSUGGESTS THE MECHANISM FOR TCR ANTAGONISM

Understanding the parameters involved in T cell activation has been co mplicated by the discovery of partial T cell agonists. Altered peptide ligands (APL) have recently shown that different subsets of T cell re sponses can be selectively activated by certain peptides, which define a hierarchy of T cell activation. For cytotoxic T cells, this hierarc hy ranges from sensitizing target cells for lysis through proliferatio n to effector cell induction. The degree of TCR down-regulation mediat ed by APL-MHC interactions correlates well with the induction of speci fic T cell effector functions. This suggests that the potential agonis t response induced by a given peptide occurs at different triggering t hresholds. To examine the relative agonist and antagonist functions of different peptides, we have investigated the ability of lymphocytic c horiomeningitis virus glycoprotein-derived APL to induce or inhibit a range of effector functions in naive CD8(+) T cells. By this, we have defined a hierarchy of peptides that display a range of properties fro m strong agonist to no agonist function. At each level, peptides that were ranked lower in this hierarchy were able to interfere or antagoni ze the induction of effector functions by higher ranking peptides. We have therefore shown that this spectrum of peptides ranging from stron g to no agonist function has an inverse gradient from strong antagonis t to no antagonist function. Moreover, the ability of the different pe ptides to inhibit TCR internalization correlated with their ranking wi thin the hierarchy. These findings support the model that antagonists are effectively preventing TCR oligomerization and functional TCR trig gering.