spacer Crystal structure of HLA-DR1/TPI(23-37) complexed with staphylococcal enterotoxin C3 variant 3B2 (SEC3-3B2)
Primary citation
Title Minor structural changes in a mutated human melanoma antigen correspond to dramatically enhanced stimulation of a CD4+ tumor-infiltrating lymphocyte line.
Authors Sundberg, E.J.search; Sawicki, M.W.search; Southwood, S.search; Andersen, P.S.search; Sette, A.search; Mariuzza, R.A.search
Journal J.MOL.BIOL.search vol:319, pag:449-461 (2002), Identifiers: PubMed ID (12051920)search DOI (10.1016/S0022-2836(02)00370-4)
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.
MeSH terms Amino Acid Sequencesearch, Antigen Presentationsearch, Antigenssearch, CD4-Positive T-Lymphocytessearch, Crystallographysearch, X-Raysearch, HLA-DR1 Antigensearch, Humanssearch, Lymphocyte Activationsearch, Melanomasearch, Modelssearch, Molecularsearch, Molecular Sequence Datasearch, Mutationsearch, Peptide Fragmentssearch, Protein Conformationsearch, Receptorssearch, Antigensearch, T-Cellsearch, Triose-Phosphate Isomerasesearch
Other entries described in this publication 1klg
Secondary citations
Title Biochemical identification of a mutated human melanoma antigen recognized by CD4+ T cells
Authors Pieper, R.search; Christian, R.E.search; Gonzales, M.I.search; Nishimura, M.I.search; Gupta, G.search; Settlage, R.E.search; Shabanowitz, J.search; Rosenberg, S.A.search; Hunt, D.F.search; Topalian, S.L.search
Journal J.EXP.MED.search vol:189, pag:757-765 (1999) DOI (10.1084/jem.189.5.757)
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