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Role of CD8 in aberrant function of cytotoxic T lymphocytes.

Kessler B, Hudrisier D, Cerottini JC, Luescher IF - J. Exp. Med. (1997)

Bottom Line: Thus agonists that were efficiently recognized exhibited rapid TCR-ligand complex dissociation, and hence a high frequency of serial TCR engagement, whereas the opposite was true for weak agonists.Surprisingly, these differences were largely accounted for by the coreceptor CD8.While it was known that CD8 substantially decreases TCR-ligand complex dissociation, we observed in this study that this effect varied considerably among ligand variants, indicating that epitope modifications can alter the CD8 contribution to TCR-ligand binding, and hence the efficiency of antigen recognition by CTL.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland.

ABSTRACT
Using H-2Kd-restricted photoprobe-specific cytotoxic T lymphocyte (CTL) clones, which permit assessment of T cell receptor (TCR)-ligand interactions by TCR photoaffinity labeling, we observed that the efficiency of antigen recognition by CTL was critically dependent on the half-life of TCR-ligand complexes. We show here that antigen recognition by CTL is essentially determined by the frequency of serial TCR engagement, except for very rapid dissociations, which resulted in aberrant TCR signaling and antagonism. Thus agonists that were efficiently recognized exhibited rapid TCR-ligand complex dissociation, and hence a high frequency of serial TCR engagement, whereas the opposite was true for weak agonists. Surprisingly, these differences were largely accounted for by the coreceptor CD8. While it was known that CD8 substantially decreases TCR-ligand complex dissociation, we observed in this study that this effect varied considerably among ligand variants, indicating that epitope modifications can alter the CD8 contribution to TCR-ligand binding, and hence the efficiency of antigen recognition by CTL.

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TCR-ligand complex dissociation kinetics on cloned T1,  S17 and S14 CTL. Aliquots of CTL, preincubated in the absence or presence of SF1.-1.1.1 Fab′ with soluble covalent complexes of Kd and  IASA-YIPSAEK(ABA)I or variants, were diluted into aliquots of DMEM  containing anti-Kd α1 mAb 20-8-4S and UV irradiated after the indicated  periods of incubation. All kinetic experiments were performed at 26°C,  except the one shown in d, which was assessed at 37°C. The TCR photoaffinity labeling observed at time 0 was defined as 100%. τ1/2 designates  the time required for 50% dissociation.
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Figure 2: TCR-ligand complex dissociation kinetics on cloned T1, S17 and S14 CTL. Aliquots of CTL, preincubated in the absence or presence of SF1.-1.1.1 Fab′ with soluble covalent complexes of Kd and IASA-YIPSAEK(ABA)I or variants, were diluted into aliquots of DMEM containing anti-Kd α1 mAb 20-8-4S and UV irradiated after the indicated periods of incubation. All kinetic experiments were performed at 26°C, except the one shown in d, which was assessed at 37°C. The TCR photoaffinity labeling observed at time 0 was defined as 100%. τ1/2 designates the time required for 50% dissociation.

Mentions: Assessment of the kinetics of TCR-ligand complex dissociation showed that for both strong agonists the dissociation was significantly faster than for the wild-type ligand (Fig. 2, a and c). In contrast, for the two weak agonists dissociation was markedly slower, even though in one case (E258A on S14 CTL) TCR-ligand binding was weak (Fig. 2, b and c). For sake of increased accuracy, these kinetics were assessed at 26°C. With S17 CTL kinetics were also measured at 37°C (Fig. 2 d), showing that on living CTL TCR-ligand complex dissociation increases considerably with temperature, as has been reported for T1 CTL (15). These findings are consistent with the concept of serial TCR engagement (21, 23, 24), namely that CTL activation depends on the frequency of serial TCR engagement, which is determined by the rate of TCR-ligand complex dissociation.


Role of CD8 in aberrant function of cytotoxic T lymphocytes.

Kessler B, Hudrisier D, Cerottini JC, Luescher IF - J. Exp. Med. (1997)

TCR-ligand complex dissociation kinetics on cloned T1,  S17 and S14 CTL. Aliquots of CTL, preincubated in the absence or presence of SF1.-1.1.1 Fab′ with soluble covalent complexes of Kd and  IASA-YIPSAEK(ABA)I or variants, were diluted into aliquots of DMEM  containing anti-Kd α1 mAb 20-8-4S and UV irradiated after the indicated  periods of incubation. All kinetic experiments were performed at 26°C,  except the one shown in d, which was assessed at 37°C. The TCR photoaffinity labeling observed at time 0 was defined as 100%. τ1/2 designates  the time required for 50% dissociation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199177&req=5

Figure 2: TCR-ligand complex dissociation kinetics on cloned T1, S17 and S14 CTL. Aliquots of CTL, preincubated in the absence or presence of SF1.-1.1.1 Fab′ with soluble covalent complexes of Kd and IASA-YIPSAEK(ABA)I or variants, were diluted into aliquots of DMEM containing anti-Kd α1 mAb 20-8-4S and UV irradiated after the indicated periods of incubation. All kinetic experiments were performed at 26°C, except the one shown in d, which was assessed at 37°C. The TCR photoaffinity labeling observed at time 0 was defined as 100%. τ1/2 designates the time required for 50% dissociation.
Mentions: Assessment of the kinetics of TCR-ligand complex dissociation showed that for both strong agonists the dissociation was significantly faster than for the wild-type ligand (Fig. 2, a and c). In contrast, for the two weak agonists dissociation was markedly slower, even though in one case (E258A on S14 CTL) TCR-ligand binding was weak (Fig. 2, b and c). For sake of increased accuracy, these kinetics were assessed at 26°C. With S17 CTL kinetics were also measured at 37°C (Fig. 2 d), showing that on living CTL TCR-ligand complex dissociation increases considerably with temperature, as has been reported for T1 CTL (15). These findings are consistent with the concept of serial TCR engagement (21, 23, 24), namely that CTL activation depends on the frequency of serial TCR engagement, which is determined by the rate of TCR-ligand complex dissociation.

Bottom Line: Thus agonists that were efficiently recognized exhibited rapid TCR-ligand complex dissociation, and hence a high frequency of serial TCR engagement, whereas the opposite was true for weak agonists.Surprisingly, these differences were largely accounted for by the coreceptor CD8.While it was known that CD8 substantially decreases TCR-ligand complex dissociation, we observed in this study that this effect varied considerably among ligand variants, indicating that epitope modifications can alter the CD8 contribution to TCR-ligand binding, and hence the efficiency of antigen recognition by CTL.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland.

ABSTRACT
Using H-2Kd-restricted photoprobe-specific cytotoxic T lymphocyte (CTL) clones, which permit assessment of T cell receptor (TCR)-ligand interactions by TCR photoaffinity labeling, we observed that the efficiency of antigen recognition by CTL was critically dependent on the half-life of TCR-ligand complexes. We show here that antigen recognition by CTL is essentially determined by the frequency of serial TCR engagement, except for very rapid dissociations, which resulted in aberrant TCR signaling and antagonism. Thus agonists that were efficiently recognized exhibited rapid TCR-ligand complex dissociation, and hence a high frequency of serial TCR engagement, whereas the opposite was true for weak agonists. Surprisingly, these differences were largely accounted for by the coreceptor CD8. While it was known that CD8 substantially decreases TCR-ligand complex dissociation, we observed in this study that this effect varied considerably among ligand variants, indicating that epitope modifications can alter the CD8 contribution to TCR-ligand binding, and hence the efficiency of antigen recognition by CTL.

Show MeSH
Related in: MedlinePlus