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Kinetics and thermodynamics of T cell receptor-autoantigen interactions in murine experimental autoimmune encephalomyelitis

Kinetics and thermodynamics of T cell receptor-autoantigen interactions in murine experimental autoimmune encephalomyelitis
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 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-Au with 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.

0027-8424
6818-6823
Garcia, K. Christopher
7d350d83-3b91-4e3f-8d04-7bac948ce89f
Radu, Caius G.
7b0cdea8-4ad8-4c89-89f7-eb6083504c1c
Ho, Joseph
6dcc1c70-95a5-473d-9361-d5d9228c459a
Ober, Raimund J.
31f4d47f-fb49-44f5-8ff6-87fc4aff3d36
Sally Ward, E.
b31c0877-8abe-485f-b800-244a9d3cd6cc
Garcia, K. Christopher
7d350d83-3b91-4e3f-8d04-7bac948ce89f
Radu, Caius G.
7b0cdea8-4ad8-4c89-89f7-eb6083504c1c
Ho, Joseph
6dcc1c70-95a5-473d-9361-d5d9228c459a
Ober, Raimund J.
31f4d47f-fb49-44f5-8ff6-87fc4aff3d36
Sally Ward, E.
b31c0877-8abe-485f-b800-244a9d3cd6cc

Garcia, K. Christopher, Radu, Caius G., Ho, Joseph, Ober, Raimund J. and Sally Ward, E. (2001) Kinetics and thermodynamics of T cell receptor-autoantigen interactions in murine experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences, 98 (12), 6818-6823. (doi:10.1073/pnas.111161198).

Record type: Article

Abstract

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-Au with 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.

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More information

Accepted/In Press date: 2 April 2001
Published date: 5 June 2001

Identifiers

Local EPrints ID: 424918
URI: http://eprints.soton.ac.uk/id/eprint/424918
ISSN: 0027-8424
PURE UUID: 5c558c14-149d-4650-b7be-a2605bfaab3c
ORCID for Raimund J. Ober: ORCID iD orcid.org/0000-0002-1290-7430
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

Catalogue record

Date deposited: 05 Oct 2018 16:30
Last modified: 26 Nov 2019 01:23

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Contributors

Author: K. Christopher Garcia
Author: Caius G. Radu
Author: Joseph Ho
Author: Raimund J. Ober ORCID iD
Author: E. Sally Ward ORCID iD

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