title: Minor structural changes in a mutated human melanoma antigen correspond to dramatically enhanced stimulation of a CD4+ tumor-infiltrating lymphocyte line.
abstract: While most immunotherapies for cancer have focused on eliciting specific CD8+ cytotoxic T lymphocyte killing of tumor cells, a mounting body of evidence suggests that stimulation of anti-tumor CD4+ T cell help may be required for highly effective therapy. Several MHC class II-restricted tumor antigens that specifically activate such CD4+ helper T lymphocytes have now been identified, including one from a melanoma tumor that is caused by a single base-pair mutation in the glycolytic enzyme triosephosphate isomerase. This mutation results in the conversion of a threonine residue to isoleucine within the antigenic epitope, concomitant with a greater than five log-fold increase in stimulation of a CD4+ tumor-infiltrating lymphocyte line. Here, we present the crystal structures of HLA-DR1 in complex with both wild-type and mutant TPI peptide antigens, the first structures of tumor peptide antigen/MHC class II complexes recognized by CD4+ T cells to be reported. These structures show that very minor changes in the binding surface for T cell receptor correspond to the dramatic differences in T cell stimulation. Defining the structural basis by which CD4+ T cell help is invoked in an anti-tumor immune response will likely aid the design of more effective cancer immunotherapies.
authors.affiliation: Center for Advanced Research in Biotechnology, W. M. Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. sundberg@umbi.umd.edu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.forename: Mark W
authors.initials: MW
authors.lastname: Sawicki
authors.forename: Scott
authors.initials: S
authors.lastname: Southwood
authors.forename: Peter S
authors.initials: PS
authors.lastname: Andersen
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018360:Crystallography, X-Ray; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D014305:Triose-Phosphate Isomerase / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
chemical_list: D000941:Antigens; D015798:HLA-DR1 Antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014305:Triose-Phosphate Isomerase