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Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor

Nature Immunology volume 8, pages 398–408 (2007)Cite this article

Abstract

Structural studies of complexes of T cell receptor (TCR) and peptide–major histocompatibility complex (MHC) have focused on TCRs specific for foreign antigens or native self. An unexplored category of TCRs includes those specific for self determinants bearing alterations resulting from disease, notably cancer. We determined here the structure of a human melanoma–specific TCR (E8) bound to the MHC molecule HLA-DR1 and an epitope from mutant triosephosphate isomerase. The structure had features intermediate between 'anti-foreign' and autoimmune TCR–peptide–MHC class II complexes that may reflect the hybrid nature of altered self. E8 manifested very low affinity for mutant triosephosphate isomerase–HLA-DR1 despite the highly tumor-reactive properties of E8 cells. A second TCR (G4) had even lower affinity but underwent peptide-specific formation of dimers, suggesting this as a mechanism for enhancing low-affinity TCR-peptide-MHC interactions for T cell activation.

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Figure 1: Recognition of wild-type and mutant TPI peptides by TIL1558 cells and by clones E8 and G4.
Figure 2: Binding of TCR E8 and G4 tetramers to wild-type TPI–DR1 and mutant TPI–DR1 complexes.
Figure 3: Structure of the E8–mutant TPI–DR1 complex and comparison with other TCR-peptide-MHC class II complexes.
Figure 4: Interactions of TCR E8 with TPI peptides and HLA-DR1.
Figure 5: Position of TCR CDR3 loops over foreign, tumor or self peptide antigens in TCR-peptide-DR complexes.
Figure 6: Conformational changes in TCR E8 and TPI-DR1 after complex formation.
Figure 7: Sedimentation-velocity analytical ultracentrifugation of linked G4-TPI-DR1 complexes, TCR G4 and mutant TPI–DR1.

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Acknowledgements

We thank D.M. Pardoll for critical reading of the manuscript; E.J. Sundberg for initial studies; Y. Yin and S. Li for assistance with peptide synthesis; and T. McMiller for assistance with T cell assays. Supported by the National Institutes of Health (AI036900 to R.A.M.), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (M.I.G. and S.L.T.) and the Cancer Research Institute (L.D.).

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Author notes

  1. Ries J Langley, Patrick H Brown, Michael I Nishimura & Suzanne L Topalian

    Present address: Present addresses: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (R.J.L.), Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda, Maryland 20892, USA (P.H.B.), Medical University of South Carolina, Hollings Cancer Center, Charleston, South Carolina 29425, USA (M.I.N.), and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA (S.L.T.).,

  2. Lu Deng and Ries J Langley: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Advanced Research in Biotechnology, WM Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, 20850, Maryland, USA

    Lu Deng, Ries J Langley, Patrick H Brown, Gang Xu, Leslie Teng, Qian Wang & Roy A Mariuzza

  2. Surgery Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Monica I Gonzales & Suzanne L Topalian

  3. Department of Surgery, University of Chicago, Chicago, 60637, Illinois, USA

    Glenda G Callender & Michael I Nishimura

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Contributions

L.D., X-ray crystallographic analyses; R.J.L., P.H.B., G.X., L.T. and Q.W., biochemical and biophysical experiments; M.I.G., G.G.C. and M.I.N., derivation and characterization of T cell clones; and S.L.T. and R.A.M., project direction.

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Correspondence to Suzanne L Topalian or Roy A Mariuzza.

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Supplementary information

Supplementary Table 1

Interactions between TCR and MHC molecules in the E8-mutTPI-DR1, HA1.7-HA-DR1 and 3A6-MBP-DR2 complexes. (PDF 84 kb)

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Deng, L., Langley, R., Brown, P. et al. Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor. Nat Immunol 8, 398–408 (2007). https://doi.org/10.1038/ni1447

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