PARTIAL SIGNALING BY CD8(-CELLS IN RESPONSE TO ANTAGONIST LIGANDS() T)

Structural variants of art agonist peptide-major histocompatibility co mplex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure an tagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transient s and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-depe ndent signal transduction, with their antagonist properties ascribed t o competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8(+) T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and parti al agonists or agonist/antagonist combinations elicit a distinctive pa ttern of early TCR-associated tyrosine phosphorylation events in CD4() T cells. We have therefore directly examined proximal TCR signaling in a CD8(+) T cell line in response to various related Ligands. TCR en gagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR-associated tyrosine phosphorylation events as se en with CD4(+) cells, including accumulation of both the p21 and p23 f orms of phosphorylated zeta, phosphorylation of CD3 epsilon, and assoc iation of phosphorylated ZAP-70 with the TCR. Two antagonists that lac ked the ability to induce any detectable CTL effector response (cytoly sis, esterase release, gamma interferon secretion, interleukin-2 recep tor alpha upregulation) were nevertheless found to also induce TCR-dep endent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta: without net phosphorylat ion of CD3 epsilon, as well as the association of nonphosphorylated ZA P-70 kinase with the receptor. These data show that variant ligands in duce similar TCR-dependent phosphorylation events in CD8(+) T cells as first observed in CD4(+) cells. More importantly, they demonstrate th at some putatively pure antagonists are actually a subset of partial a gonists able to induce intracellular biochemical changes through the T CR. This delivery of a partial signal by antagonists raises the possib ility that antagonism in some cases may result from active interferenc e with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes.