Kinetics and Thermodynamics of T Cell Receptor-Autoantigen Interactions in Murine Experimental Autoimmune Encephalomyelitis

In the current study, cellular and molecular approaches have been used to analyze the biophysical nature of T cell receptor (TCR)-peptide MHC (pMHC) interactions for two autoreactive TCRs. These two TCRs recognize the N-terminal epitope of myelin basic protein (MBP1-11) bound to the MHC class II pro...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-06, Vol.98 (12), p.6818-6823
Main Authors: Garcia, K. Christopher, Radu, Caius G., Ho, Joseph, Ober, Raimund J., Ward, E. Sally
Format: Article
Language:English
Subjects:
Animals
Autoantigens - metabolism
Biological Sciences
Cell Line
Cell lines
Disease models
Encephalitis
Encephalomyelitis, Autoimmune, Experimental - immunology
Hybridomas
Hybridomas - immunology
Immunity
Immunology
Kinetics
Ligands
Mice
myelin basic protein
Myelin Basic Protein - metabolism
Peptide Fragments - metabolism
Peptides
Receptors, Antigen, T-Cell - metabolism
Rodents
T cell antigen receptors
T lymphocytes
Thermodynamics
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Summary:In the current study, cellular and molecular approaches have been used to analyze the biophysical nature of T cell receptor (TCR)-peptide MHC (pMHC) interactions for two autoreactive TCRs. These two TCRs recognize the N-terminal epitope of myelin basic protein (MBP1-11) bound to the MHC class II protein, I-Au, and are associated with murine experimental autoimmune encephalomyelitis. Mice transgenic for the TCRs have been generated and characterized in other laboratories. These analyses indicate that the mice either develop encephalomyelitis spontaneously (172.10 TCR) or only if immunized with autoantigen in adjuvant (1934.4 TCR). Here, we show that the 172.10 TCR binds MBP1-11: I-Auwith a 4-5-fold higher affinity than the 1934.4 TCR. Consistent with the higher affinity, 172.10 T hybridoma cells are significantly more responsive to autoantigen than 1934.4 cells. The interaction of the 172.10 TCR with cognate ligand is more entropically unfavorable than that of the 1934.4 TCR, indicating that the 172.10 TCR undergoes greater conformational rearrangements upon ligand binding. The studies therefore suggest a correlation between the strength and plasticity of a TCR-pMHC interaction and the frequency of spontaneous disease in the corresponding TCR transgenic mice. The comparative analysis of these two TCRs has implications for understanding autoreactive T cell recognition and activation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.111161198