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Agonist-induced T cell receptor down-regulation: molecular requirements and dissociation from T cell activation
M Salio1, S Valitutti, A Lanzavecchia
1Basel Institute for Immunology, Switzerland. salio@bii.ch
Abstract:
T cell receptor (TCR) down-regulation is a consequence of specific receptor engagement and plays an important role in modulating the T cell response. We have investigated the role of protein kinase C (PKC) and protein tyrosine kinases (PTK) in the induction of TCR down-regulation. We report that the mutation of S126 in the CD3-gamma chain that is known to inhibit phorbol-12-myristate 13-acetate-induced TCR down-regulation does not affect down-regulation induced by a specific agonist. In addition, agonist-induced TCR down-regulation is not affected by blockade or depletion of PKC, neither by blockade or lack of PTK, while the same treatments efficiently interfere with T cell activation. These results demonstrate that TCR down-regulation is induced by early events which follow specific engagement by an agonist and can be dissociated from those required for full T cell activation.
Insights
T cell receptor (TCR) down-regulation, crucial for T cell response, is triggered by early signaling events following specific agonist engagement. This process is independent of protein kinase C (PKC) and protein tyrosine kinases (PTK) pathways.
Area of Science:
- Immunology
- Cell Signaling
Background:
- T cell receptor (TCR) down-regulation modulates T cell responses after receptor engagement.
- Protein kinase C (PKC) and protein tyrosine kinases (PTK) are implicated in T cell signaling pathways.
Purpose of the Study:
- To investigate the role of PKC and PTK in agonist-induced TCR down-regulation.
- To determine if TCR down-regulation is linked to T cell activation pathways.
Main Methods:
- Mutational analysis of the CD3-gamma chain (S126).
- Pharmacological blockade and depletion of PKC and PTK.
- Assessment of TCR down-regulation and T cell activation in response to specific agonists.
Main Results:
- Mutation of S126 in CD3-gamma did not inhibit agonist-induced TCR down-regulation.
- PKC blockade/depletion and PTK blockade/lack did not affect agonist-induced TCR down-regulation.
- These treatments, however, effectively inhibited T cell activation.
Conclusions:
- Agonist-induced TCR down-regulation is initiated by early signaling events distinct from those required for T cell activation.
- The pathways regulating TCR down-regulation are separable from those mediating full T cell activation.