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

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TitleStructural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor.
Publication TypeJournal Article
Year of Publication2007
AuthorsDeng, L, Langley, RJ, Brown, PH, Xu, G, Teng, L, Wang, Q, Gonzales, MI, Callender, GG, Nishimura, MI, Topalian, SL, Mariuzza, RA
JournalNat Immunol
Volume8
Issue4
Pagination398-408
Date Published2007 Apr
ISSN1529-2908
KeywordsAmino Acid Sequence, Cell Line, Tumor, Crystallography, X-Ray, Epitopes, HLA-DR1 Antigen, Humans, Melanoma, Models, Molecular, Molecular Sequence Data, Point Mutation, Protein Conformation, Receptors, Antigen, T-Cell, Surface Plasmon Resonance, Triose-Phosphate Isomerase, Ultracentrifugation
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.

DOI10.1038/ni1447
Alternate JournalNat. Immunol.
PubMed ID17334368
Grant ListAI036900 / AI / NIAID NIH HHS / United States
R37 AI036900-14 / AI / NIAID NIH HHS / United States