title: HER-2 peptides p776 and F7, N-terminal-linked with Ii-Key tetramer (LRMK) help the proliferation of E75-TCR+ cells: The dependency of help on the side chains of LRMK-extended peptide pointed towards the T cell receptor.
abstract: The objective of this study was to determine whether peptides consisting of the Ii-Key peptide LRMK linked to the N-terminal ends of HER-2 peptides would stimulate the expansion of antigen-specific E75-TCR+CD8+ cells. The peptides tested were N-acetylated and linked to an alpha-amide at the C-terminus; some of the peptides contained epsilon-aminovaleric acid (Ava) between the LRMK and the HER-2 peptide. Of the seven LRMK-HER-2 peptides tested to date, three effectively induced IFN-gamma production by peripheral blood mononuclear cells (PBMCs) from healthy donors and women with ductal carcinoma in situ. A fusion peptide, LRMK-Ava-HER-2(777-789), was more immunogenic than the natural HER-2(777-789) antigen, G89, with regard to IFN-gamma production. In combination with the CD8-activating peptide E75 [HER-2(369-377)] LRMK-p776 and LRMK-Ava-F7 induced the proliferation of E75-TCR(Med+Hi) CD8+ cells to a greater extent than did 1,000 or 5,000 nM of E75 alone, respectively. The induction effects were strongest at 600 nM for LRMK-p776 and 3,000 nM for LRMK-Ava-F7. At 3,000 nM, LRMK-p776 was cytotoxic to PBMCs. LRMK-p776 and F7 had a similar specificity and preferences for binding HLA-DR molecules. The molecular modeling of HLA-DR:LRMK-p776 and HLA-DR:LRMK-Ava-F7 complexes revealed the side chains of the peptides, which pointed towards the T-cell receptor. Differences in side chain orientation introduced by various N-terminal extensions of MHC class II-bound peptides should be important for directing CD4+ cells to stimulate CD8+ cells or for eliminating regulatory T cells in cancer immunotherapy.
authors.affiliation: Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishiyama
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsueda
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuda
authors.forename: Constantin G
authors.initials: CG
authors.lastname: Ioannides
mesh_terms: D000595:Amino Acid Sequence; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000276:immunology* / Q000473:pathology; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; C045084:invariant chain