Article abstract
Nature Immunology 8, 398 - 408 (2007)
Published online: 4 March 2007 | doi:10.1038/ni1447
Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor
Lu Deng1,5, Ries J Langley1,4,5, Patrick H Brown1,4, Gang Xu1, Leslie Teng1, Qian Wang1, Monica I Gonzales2, Glenda G Callender3, Michael I Nishimura3,4, Suzanne L Topalian2,4 & Roy A Mariuzza1
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.
- Center for Advanced Research in Biotechnology, WM Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850, USA.
- Surgery Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Department of Surgery, University of Chicago, Chicago, Illinois 60637, USA.
- 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.).
- These authors contributed equally to this work.
Correspondence to: Suzanne L Topalian2,4 e-mail: stopali1@jhmi.edu
Correspondence to: Roy A Mariuzza1 e-mail: mariuzza@carb.nist.gov
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