Partial signaling by CD8+ T cells in response to antagonist ligands.

Abstract

SummaryStructural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8 + T cells can induce positive selection of thymocytes, implying active induction ofT cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern 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 engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR-associated tyrosine phosphorylation events as seen with CD4 + cells, including accumulation of both the p21 and p23 forms of phosphorylated ~, phosphorylation of CD3e, and association ofphosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, ~/interferon secretion, interleukin-2 receptor o~ upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-~ without net phosphorylation of CD3e, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR-dependent phosphorylation events in CD8 + T cells as first observed in CD4 + cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellnlar biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation ofeffector 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.

Direct Phenotypic Analysis of Human MHC Class I Antigen Presentation: Visualization, Quantitation, and In Situ Detection of Human Viral Epitopes Using Peptide-Specific, MHC-Restricted Human Recombinant Antibodies

“…8A and Table I). Specific ligand detection sensitivity was observed with as low as 100 complexes per cell (when cells were pulsed with 6 nM peptide) and reached saturation at ϳ1.1-1.2 ϫ 10 5 complexes per cell at high peptide concentration of 25-50 M. These results demonstrate that the sensitivity of ligand detection by T3F2 is in the same range of the minimal concentrations of peptides needed to elicit measurable cytokine secretion (IL-2 or IFN-␥) from T cell hybridomas or target cell lysis by CD8 ϩ CTL lines (36,37).…”

Galectin-1 Tunes TCR Binding and Signal Transduction to Regulate CD8 Burst Size

“…In support of this suggestion, rgal-1 can induce partial TCR -chain phosphorylation and antagonize processive -chain phosphorylation (30), a signaling signature associated with TCR antagonist-ligand activity (31,32). The rgal-1 also antagonizes polarized synaptic lipid raft clustering (30) and can selectively influence TCR functional outcome (8,26,30,33) in some CD4/ class II-restricted cells and hybridomas.…”

A correlation between function and selected measures of T cell avidity in influenza virus‐specific CD8+ T cell responses

“…Thus, while correlations have been made between increased T cell "avidity" and functional responsiveness of T cells [5][6][7][8], the definition of avidity is arbitrary and usually based on the measurement of only one indicator. Given that each avidity measure provides information on a distinct feature of T cell interactions, it is important to determine the relationship between them, and to identify correlations between these indicators and the quality of the CD8 + T cell response.…”