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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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Antigen recognition, IFN-γ production and TCR-ligand  binding for IASA-YIPSAEK(ABA)I (wt) and variants on cloned CTL.  The normalized relative antigenic activities (cytotoxicity) and TCR-ligand binding at 26°C are shown as open and full bars, respectively (a),  and the IFN-γ production as open bars (b). All values were normalized  relative to IASA-YIPSAEK(ABA)I. The cases for which the CTL response was ⩾5-fold lower than TCR-ligand binding are shown in red  and those for which it was ⩾5-fold higher in green. TCR antagonists are  shown in purple. The variants tested include IASA-YIASAEK(ABA)I  (P255A), IASA-YIPSAAK(ABA)I (E258A), IASA-YISSAEK(ABA)I  (P255S), IASA-YIPAAEK(ABA)I (S256A), IASA-YILSAEK(ABA)I  (P255L), and the CTL clones T1, S14, and S17. Some of the experiments  were performed in the presence of SF1-1.1.1 Fab′. Each experiment was  performed in triplicates and the mean values and standard deviations were  calculated from at least two experiments.
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Figure 1: Antigen recognition, IFN-γ production and TCR-ligand binding for IASA-YIPSAEK(ABA)I (wt) and variants on cloned CTL. The normalized relative antigenic activities (cytotoxicity) and TCR-ligand binding at 26°C are shown as open and full bars, respectively (a), and the IFN-γ production as open bars (b). All values were normalized relative to IASA-YIPSAEK(ABA)I. The cases for which the CTL response was ⩾5-fold lower than TCR-ligand binding are shown in red and those for which it was ⩾5-fold higher in green. TCR antagonists are shown in purple. The variants tested include IASA-YIASAEK(ABA)I (P255A), IASA-YIPSAAK(ABA)I (E258A), IASA-YISSAEK(ABA)I (P255S), IASA-YIPAAEK(ABA)I (S256A), IASA-YILSAEK(ABA)I (P255L), and the CTL clones T1, S14, and S17. Some of the experiments were performed in the presence of SF1-1.1.1 Fab′. Each experiment was performed in triplicates and the mean values and standard deviations were calculated from at least two experiments.

Mentions: To assess the significance of TCR-ligand complex dissociation for CTL function, we selected two cases, in which antigen recognition was more efficient than TCR-ligand binding (strong agonists) (peptide derivative variant P255A on T1 CTL and S256A on S17 CTL) and two examples where recognition was less efficient than binding (weak agonists) (P255S on S17 CTL and E258A on S14 CTL) (Fig. 1 a). Since perforin dependent cytotoxicity, as mainly assessed in the used chromium release assay, is a rapid CTL response and takes place at very low peptide concentrations (20, 21), we also assessed the interferon-γ (IFN-γ) response, which requires higher peptide concentrations and sustained TCR signaling for extended periods of time (21). In spite of these differences both CTL responses were remarkably similar, except that on S14 CTL for E258A the IFN-γ production was more efficient than cytotoxicity (Fig. 1 b). Occasional divergences between cytolytic and IFN-γ CTL responses among peptide variants have also been observed in other systems (24).


Role of CD8 in aberrant function of cytotoxic T lymphocytes.

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

Antigen recognition, IFN-γ production and TCR-ligand  binding for IASA-YIPSAEK(ABA)I (wt) and variants on cloned CTL.  The normalized relative antigenic activities (cytotoxicity) and TCR-ligand binding at 26°C are shown as open and full bars, respectively (a),  and the IFN-γ production as open bars (b). All values were normalized  relative to IASA-YIPSAEK(ABA)I. The cases for which the CTL response was ⩾5-fold lower than TCR-ligand binding are shown in red  and those for which it was ⩾5-fold higher in green. TCR antagonists are  shown in purple. The variants tested include IASA-YIASAEK(ABA)I  (P255A), IASA-YIPSAAK(ABA)I (E258A), IASA-YISSAEK(ABA)I  (P255S), IASA-YIPAAEK(ABA)I (S256A), IASA-YILSAEK(ABA)I  (P255L), and the CTL clones T1, S14, and S17. Some of the experiments  were performed in the presence of SF1-1.1.1 Fab′. Each experiment was  performed in triplicates and the mean values and standard deviations were  calculated from at least two experiments.
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Related In: Results  -  Collection

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Figure 1: Antigen recognition, IFN-γ production and TCR-ligand binding for IASA-YIPSAEK(ABA)I (wt) and variants on cloned CTL. The normalized relative antigenic activities (cytotoxicity) and TCR-ligand binding at 26°C are shown as open and full bars, respectively (a), and the IFN-γ production as open bars (b). All values were normalized relative to IASA-YIPSAEK(ABA)I. The cases for which the CTL response was ⩾5-fold lower than TCR-ligand binding are shown in red and those for which it was ⩾5-fold higher in green. TCR antagonists are shown in purple. The variants tested include IASA-YIASAEK(ABA)I (P255A), IASA-YIPSAAK(ABA)I (E258A), IASA-YISSAEK(ABA)I (P255S), IASA-YIPAAEK(ABA)I (S256A), IASA-YILSAEK(ABA)I (P255L), and the CTL clones T1, S14, and S17. Some of the experiments were performed in the presence of SF1-1.1.1 Fab′. Each experiment was performed in triplicates and the mean values and standard deviations were calculated from at least two experiments.
Mentions: To assess the significance of TCR-ligand complex dissociation for CTL function, we selected two cases, in which antigen recognition was more efficient than TCR-ligand binding (strong agonists) (peptide derivative variant P255A on T1 CTL and S256A on S17 CTL) and two examples where recognition was less efficient than binding (weak agonists) (P255S on S17 CTL and E258A on S14 CTL) (Fig. 1 a). Since perforin dependent cytotoxicity, as mainly assessed in the used chromium release assay, is a rapid CTL response and takes place at very low peptide concentrations (20, 21), we also assessed the interferon-γ (IFN-γ) response, which requires higher peptide concentrations and sustained TCR signaling for extended periods of time (21). In spite of these differences both CTL responses were remarkably similar, except that on S14 CTL for E258A the IFN-γ production was more efficient than cytotoxicity (Fig. 1 b). Occasional divergences between cytolytic and IFN-γ CTL responses among peptide variants have also been observed in other systems (24).

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