Related Experiment Videos
Cross-antagonism of a T cell clone expressing two distinct T cell receptors
B N Dittel1, I Stefanova, R N Germain
1Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA. bonnie.dittel@yale.edu
Abstract:
Inhibition of T cell activation can be mediated by analogs of the original antigenic peptide (TCR antagonists). Here, a T cell clone expressing two distinct TCR was used to investigate whether such inhibition involves an active mechanism by examining whether an antagonist for one TCR could influence responses stimulated by the other TCR engaging its agonist. Our results demonstrate functional cross-inhibition under these conditions involving the ability of antagonist: TCR interactions to diminish Lck enzymatic activity associated with the agonist-recognizing second TCR, apparently through enhancement of SHP-1 association with these receptors. Our findings reveal that inhibition of cellular responses by antagonists arises at least in part from active negative regulation of proximal TCR signaling and identify elements of the biochemical process.
Insights
T cell activation can be actively inhibited. T cell receptor (TCR) antagonists targeting one TCR can cross-inhibit another TCR
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- T cell activation is crucial for adaptive immunity.
- T cell receptor (TCR) antagonists, analogs of antigenic peptides, can inhibit T cell activation.
- The precise mechanisms underlying TCR antagonist-mediated inhibition are not fully elucidated.
Purpose of the Study:
- To investigate whether TCR antagonists mediate inhibition through an active mechanism.
- To determine if an antagonist for one TCR can influence responses mediated by a distinct TCR on the same cell.
- To elucidate the molecular pathways involved in TCR antagonist-induced cellular inhibition.
Main Methods:
- Utilized a T cell clone engineered to express two distinct T cell receptors (TCRs).
- Examined the effect of a TCR antagonist, specific for one TCR, on cellular responses to an agonist peptide stimulating the second TCR.
- Assessed Lck enzymatic activity and SHP-1 association with TCRs following antagonist and agonist stimulation.
Main Results:
- Demonstrated functional cross-inhibition, where an antagonist for one TCR diminished responses to an agonist stimulating a second TCR.
- Observed that antagonist:TCR interactions reduced Lck enzymatic activity associated with the agonist-recognizing TCR.
- Found evidence suggesting enhanced association of SHP-1 phosphatase with TCRs upon antagonist engagement.
Conclusions:
- TCR antagonist-mediated inhibition of T cell activation involves an active, negative regulatory mechanism.
- This inhibition impacts proximal TCR signaling by modulating Lck activity and SHP-1 recruitment.
- The findings identify key biochemical elements in the process of TCR antagonist-induced T cell inhibition.