Minor structural changes in a mutated human melanoma antigen correspond to dramatically enhanced stimulation of a CD4+ tumor-infiltrating lymphocyte line.

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TitleMinor structural changes in a mutated human melanoma antigen correspond to dramatically enhanced stimulation of a CD4+ tumor-infiltrating lymphocyte line.
Publication TypeJournal Article
Year of Publication2002
AuthorsSundberg, EJ, Sawicki, MW, Southwood, S, Andersen, PS, Sette, A, Mariuzza, RA
JournalJ Mol Biol
Volume319
Issue2
Pagination449-61
Date Published2002 May 31
ISSN0022-2836
KeywordsAmino Acid Sequence, Antigen Presentation, Antigens, CD4-Positive T-Lymphocytes, Crystallography, X-Ray, HLA-DR1 Antigen, Humans, Lymphocyte Activation, Melanoma, Models, Molecular, Molecular Sequence Data, Mutation, Peptide Fragments, Protein Conformation, Receptors, Antigen, T-Cell, Triose-Phosphate Isomerase
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.

DOI10.1016/S0022-2836(02)00370-4
Alternate JournalJ. Mol. Biol.
PubMed ID12051920
Grant ListAI36900 / AI / NIAID NIH HHS / United States
AI49564 / AI / NIAID NIH HHS / United States