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PNAS | June 5, 2001 | vol. 98 | no. 12 | 6818-6823
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Immunology
 Kinetics and thermodynamics of T cell receptor- autoantigen interactions in murine experimental autoimmune encephalomyelitis

K. Christopher Garcia*,dagger , Caius G. Radudagger ,Dagger , Joseph Ho*, Raimund J. Ober§, and E. Sally WardDagger ,§,

Dagger  Center for Immunology and § Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8576; and * Departments of Microbiology and Immunology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305-5124

Communicated by Hugh O. McDevitt, Stanford University School of Medicine, Stanford, CA, April 2, 2001 (received for review December 1, 2000)

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.

dagger K.C.G. and C.G.R. contributed equally to this work.

To whom reprint requests should be addressed. E-mail: sally{at}skylab.swmed.edu.

www.pnas.org/cgi/doi/10.1073/pnas.111161198
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