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Inhibition of antigen-specific T cell activation by staphylococcal enterotoxins
J E Dowd1, R N Jenkins, D R Karp
1Simmons Arthritis Research Center, University of Texas Southwestern Medical Center at Dallas 75235.
Abstract:
The staphylococcal enterotoxins SEA, SEB, SEC2, and TSST-1 bind to MHC class II molecules and stimulate polyclonal T cell populations on the basis of the expression of responsive TCR V beta domains. CL-1 is a human T cell clone that is specific for a peptide derived from influenza hemagglutinin (HA 307-319) presented in the context of HLA-DR1. CL-1 expresses the TCR V beta 13.1 domain, and does not respond to SEA, SEB, or TSST-1. This T cell was used to test the effect of nonstimulatory staphylococcal enterotoxins on a response to antigenic peptide. These toxins inhibit peptide-specific activation of CL-1 in a concentration-dependent manner. These toxins also inhibit the response of an HLA-DR1-specific alloreactive T cell clone. This inhibition seems to be a result of impaired access of TCR to the MHC/peptide complex rather than negative signaling by toxin via class II interaction or induction of T cell anergy. SEA, but neither SEB nor TSST-1 impedes avidin access to a biotin group attached to the amino terminus of HA 307-319. SEA partially impairs access of avidin to HA peptide biotinylated at residue 313, but is unable to inhibit avidin access to biotin at residue 318. This demonstrates that SEA binds to HLA-DR molecules that have also bound the antigenic peptide and suggests a topology for the interaction of SEA with class II, whereby the toxin interferes with peptide/MHC-TCR contact.
Insights
Staphylococcal enterotoxins hinder T cell responses to specific peptides by blocking T cell receptor access to the peptide-MHC complex. This mechanism, particularly with SEA, impacts immune recognition and activation pathways.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Staphylococcal enterotoxins (SEs) are superantigens that bind MHC class II molecules, activating T cells.
- T cell activation is mediated by the T cell receptor (TCR) interacting with peptide-MHC complexes.
Purpose of the Study:
- To investigate the inhibitory effect of non-stimulatory staphylococcal enterotoxins on peptide-specific T cell activation.
- To elucidate the mechanism by which these toxins interfere with T cell responses.
Main Methods:
- Utilized a human T cell clone (CL-1) specific for an influenza hemagglutinin peptide presented by HLA-DR1.
- Assessed the impact of SEs on peptide-specific T cell activation and TCR-MHC/peptide complex interaction.
- Employed biotinylation assays to map toxin binding sites on the peptide-MHC complex.
Main Results:
- Non-stimulatory SEs, including SEA, inhibited peptide-specific T cell activation in a dose-dependent manner.
- SEA was shown to impede TCR access to the peptide-MHC complex, suggesting a steric hindrance mechanism.
- SEA's binding to HLA-DR1 was mapped to interfere with TCR contact with the antigenic peptide.
Conclusions:
- Staphylococcal enterotoxins can inhibit T cell responses by physically blocking TCR access to peptide-MHC complexes.
- This interaction highlights a novel mechanism of immune modulation by superantigens, distinct from direct T cell signaling.
- Understanding this interaction is crucial for developing strategies to control T cell-mediated inflammatory diseases.