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Title: Structural Basis for the Recognition of Mutant Self by a Tumor-Specific, MHC Class II-Restricted T Cell Receptor

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.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930400
Report Number(s):
BNL-81126-2008-JA
Journal ID: ISSN 1529-2908; TRN: US200904%%680
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Immunology; Journal Volume: 8
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AFFINITY; ANTIGENS; DIMERS; HISTOCOMPATIBILITY COMPLEX; IMMUNOGLOBULINS; LYMPHOCYTES; MUTANTS; NEOPLASMS; RECEPTORS; national synchrotron light source

Citation Formats

Deng,L., Langley, R., Brown, P., Xu, G., Teng, L., Wang, Q., Gonzales, M., Callender, G., Nishimura, M., and et al. Structural Basis for the Recognition of Mutant Self by a Tumor-Specific, MHC Class II-Restricted T Cell Receptor. United States: N. p., 2007. Web. doi:10.1038/ni1447.
Deng,L., Langley, R., Brown, P., Xu, G., Teng, L., Wang, Q., Gonzales, M., Callender, G., Nishimura, M., & et al. Structural Basis for the Recognition of Mutant Self by a Tumor-Specific, MHC Class II-Restricted T Cell Receptor. United States. doi:10.1038/ni1447.
Deng,L., Langley, R., Brown, P., Xu, G., Teng, L., Wang, Q., Gonzales, M., Callender, G., Nishimura, M., and et al. Mon . "Structural Basis for the Recognition of Mutant Self by a Tumor-Specific, MHC Class II-Restricted T Cell Receptor". United States. doi:10.1038/ni1447.
@article{osti_930400,
title = {Structural Basis for the Recognition of Mutant Self by a Tumor-Specific, MHC Class II-Restricted T Cell Receptor},
author = {Deng,L. and Langley, R. and Brown, P. and Xu, G. and Teng, L. and Wang, Q. and Gonzales, M. and Callender, G. and Nishimura, M. and et al.},
abstractNote = {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.},
doi = {10.1038/ni1447},
journal = {Nature Immunology},
number = ,
volume = 8,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}