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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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Epitope modifications alter the contribution of CD8 to  TCR-ligand binding. The degree of CD8 participation in TCR-ligand  binding is expressed as the ratio of TCR-ligand binding in the absence,  divided by the binding in the presence of SF1-1.1.1 Fab′ (a). The surface  expression of TCR and CD8 was assessed by flow cytometry after staining with antibodies H57-597 and H35-17, respectively. The values indicate mean fluorescence intensities for a representative experiment. (b) Different ligand variants exhibit different ratios of TCR-α versus -β chain  TCR photoaffinity labeling on T1 and S17 CTL. An autoradiogram of  SDS-PAGE (10%, reducing conditions) of a representative experiment is  shown.
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Figure 4: Epitope modifications alter the contribution of CD8 to TCR-ligand binding. The degree of CD8 participation in TCR-ligand binding is expressed as the ratio of TCR-ligand binding in the absence, divided by the binding in the presence of SF1-1.1.1 Fab′ (a). The surface expression of TCR and CD8 was assessed by flow cytometry after staining with antibodies H57-597 and H35-17, respectively. The values indicate mean fluorescence intensities for a representative experiment. (b) Different ligand variants exhibit different ratios of TCR-α versus -β chain TCR photoaffinity labeling on T1 and S17 CTL. An autoradiogram of SDS-PAGE (10%, reducing conditions) of a representative experiment is shown.

Mentions: A striking finding of our study is that the contribution of CD8 to TCR-ligand binding varied not only among CTL clones, but also among epitope variants on given clones (Fig. 4 a). While the former differences can be explained in part by variations in CD8 and TCR expression (Fig. 4 a), the latter indicate that epitope modifications can alter the avidity of CD8 participation in TCR-ligand binding. This explains, at least in part, why blocking of CD8 accelerated TCR-ligand complex dissociation in a diverse manner, and why one cannot reliably predict from the avidity of TCR-ligand binding the dissociation rates and hence the functional phenotype of epitope variants (Figs. 1 and 2 and reference 4). Moreover, several ligand variants displayed different ratios of TCR α versus β chain photoaffinity labeling (Fig. 4 b). Similar findings were obtained at 0–4°C (unpublished data), i.e., in the absence of metabolically active cellular processes, suggesting that epitope modification can induce either conformational changes in TCR or slightly alter the orientation of TCR-ligand binding, as a result of which CD8 may participate more or less avidly in TCR-ligand binding. This view is consistent with the observation that anti-TCR mAb and their Fab′ can substantially affect T cell responses (11, 12), and suggests that the conformational changes induced by such reagents, can affect T cell function by interfering with TCR-coreceptor cooperation. It is also interesting to note that TCR-ligand binding apparently can induce structural changes in the α3 domain of MHC class I molecules, which may alter their interaction with CD8 (27, 28).


Role of CD8 in aberrant function of cytotoxic T lymphocytes.

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

Epitope modifications alter the contribution of CD8 to  TCR-ligand binding. The degree of CD8 participation in TCR-ligand  binding is expressed as the ratio of TCR-ligand binding in the absence,  divided by the binding in the presence of SF1-1.1.1 Fab′ (a). The surface  expression of TCR and CD8 was assessed by flow cytometry after staining with antibodies H57-597 and H35-17, respectively. The values indicate mean fluorescence intensities for a representative experiment. (b) Different ligand variants exhibit different ratios of TCR-α versus -β chain  TCR photoaffinity labeling on T1 and S17 CTL. An autoradiogram of  SDS-PAGE (10%, reducing conditions) of a representative experiment is  shown.
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Related In: Results  -  Collection

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

Figure 4: Epitope modifications alter the contribution of CD8 to TCR-ligand binding. The degree of CD8 participation in TCR-ligand binding is expressed as the ratio of TCR-ligand binding in the absence, divided by the binding in the presence of SF1-1.1.1 Fab′ (a). The surface expression of TCR and CD8 was assessed by flow cytometry after staining with antibodies H57-597 and H35-17, respectively. The values indicate mean fluorescence intensities for a representative experiment. (b) Different ligand variants exhibit different ratios of TCR-α versus -β chain TCR photoaffinity labeling on T1 and S17 CTL. An autoradiogram of SDS-PAGE (10%, reducing conditions) of a representative experiment is shown.
Mentions: A striking finding of our study is that the contribution of CD8 to TCR-ligand binding varied not only among CTL clones, but also among epitope variants on given clones (Fig. 4 a). While the former differences can be explained in part by variations in CD8 and TCR expression (Fig. 4 a), the latter indicate that epitope modifications can alter the avidity of CD8 participation in TCR-ligand binding. This explains, at least in part, why blocking of CD8 accelerated TCR-ligand complex dissociation in a diverse manner, and why one cannot reliably predict from the avidity of TCR-ligand binding the dissociation rates and hence the functional phenotype of epitope variants (Figs. 1 and 2 and reference 4). Moreover, several ligand variants displayed different ratios of TCR α versus β chain photoaffinity labeling (Fig. 4 b). Similar findings were obtained at 0–4°C (unpublished data), i.e., in the absence of metabolically active cellular processes, suggesting that epitope modification can induce either conformational changes in TCR or slightly alter the orientation of TCR-ligand binding, as a result of which CD8 may participate more or less avidly in TCR-ligand binding. This view is consistent with the observation that anti-TCR mAb and their Fab′ can substantially affect T cell responses (11, 12), and suggests that the conformational changes induced by such reagents, can affect T cell function by interfering with TCR-coreceptor cooperation. It is also interesting to note that TCR-ligand binding apparently can induce structural changes in the α3 domain of MHC class I molecules, which may alter their interaction with CD8 (27, 28).

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