Abstract
Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide–major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.
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Acknowledgements
This paper is dedicated to the memory of D.C. Wiley. We thank V. Stojanoff, M. Allaire (beamline X6A), A. Soares, D. Schneider (beamline X12B), A. Saxena and H. Robinson (beamline X29) at Brookhaven National Laboratories for support; M. Eck for access to X-ray facilities at the Dana-Farber Cancer Institute; K. Arnett, M. Call and S. Turley for reading the manuscript; T. Springer and T. Xiao for help and advice in evaluating Fluidigm crystallization chips; D. Zaller for the S2 cell line expressing HLA-DM; and L. Stern and K.C. Garcia for discussions. Supported by the National Institutes of Health (AI045757 and AI064177 to K.W.W.).
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Supplementary Fig. 1
Ribbon diagram of the structure of the complex composed of HLA-DR2 (blue), peptide (green), Ob.1A12 TCR Vα domain (yellow) as well as Ob.1A12 TCR Vβ and Cβ domains (red). (PDF 260 kb)
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Hahn, M., Nicholson, M., Pyrdol, J. et al. Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol 6, 490–496 (2005). https://doi.org/10.1038/ni1187
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DOI: https://doi.org/10.1038/ni1187
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