Transient alteration of T cell fine specificity by a strong primary stimulus correlates with T cell receptor down-regulation

Abstract

P14 mice expressing a transgenic TCR specific for the lymphocytic choriomeningitis virus glycoprotein p33 epitope were used to study the induction of CTL effector activity by a variety of ligands. Surprisingly, p33 variants which are weaker agonists for the P14 TCR than the wild-type p33 peptide were able to induce more potent effectors with a broader range of cytolytic specificity. Similarly, low concentrations of p33 were more effective than higher concentrations. These results correlated with no or only moderate TCR down-regulation by variants of p33 and low p33 concentrations. This phenotype observed after 18 h of culture was transient as progressive restoration of reactivity was observed at 42 or 66 h in the cultures stimulated with high p33 concentrations and this correlated with recovery of TCR surface levels. TCR down-regulation was blocked by src family kinase inhibitors. These findings indicate that the specificity of a T cell can be fine-tuned by the nature of the primary stimulus correlating with surface TCR level and imply an important role for src family kinases in the differential regulation of surface TCR levels upon TCR engagement by different ligand/MHC complexes.

Directex vivo analysis reveals distinct phenotypic patterns of HIV-specific CD8+ T lymphocyte activation in response to therapeutic manipulation of virus load

“…The interaction of the TCR with its ligand leads to phosphorylation of tyrosine residues in the immune receptor tyrosine-based activation motifs (ITAM) of the CD3 chains and to internalization of the TCR [9,10]. TCR down-regulation after antigen encounter occurs rapidly, is long-lasting and believed to be intimately tied to T cell activation, serial triggering of receptors and desensitization of stimulated cells [4,7,11]. In vitro, this phenotype of downregulated TCR on recently triggered T cells is reversible after prolonged culture periods.…”

Activating CTL precursors to reveal CTL function without skewing the repertoire byin vitro expansion

“…6B). These differences may be explained by apoptosis of high‐avidity CTL 9 and/or TCR down‐modulation 10 in response to high peptide concentration. Thus, even a 12‐h stimulation with too high a peptide concentration can alter the range of CTL avidities detected.…”

Syndecan‐2 can promote clearance of T‐cell receptor/CD3 from the cell surface

“…9 The downregulation of triggered TCR/CD3 and its subsequent degradation are considered necessary events for limiting sustained TCR signalling, resulting in decreased sensitivity of the T-cell to the antigen. 9,36,[39][40][41] In addition to TSG101, other proteins mechanistically associated with the TCR/CD3 down-regulation process have been identified. Mature T cells, when they lack CD2associated protein 41 or intra-flagellar transport proteins, 42 show an altered balance between surface and intracellular TCR/CD3.…”

“…Recognition of ubiquitinated TCR/CD3 by TSG101 leads to receptor translocation into multivesicular bodies and lysosomes, which causes receptor dephosphorylation and degradation . The down‐regulation of triggered TCR/CD3 and its subsequent degradation are considered necessary events for limiting sustained TCR signalling, resulting in decreased sensitivity of the T‐cell to the antigen …”