title: The signal peptide of the tumor-shared antigen midkine hosts CD4+ T cell epitopes.
abstract: BACKGROUND
  The CD4 T cell response to the tumor antigen Midkine was unknown.
  
  
  RESULTS
  Most of the T cell response to Midkine relies on T cell epitopes contained in its signal peptide.
  
  
  CONCLUSIONS
  The signal peptide of Midkine is accessible to HLA class II pathway for CD4 T cell presentation.
  
  
  CONCLUSIONS
  It is a new function for signal peptides to contribute to tumor-specific CD4 T cell response. Because of the key role of CD4 T cell response in immunity to tumors, we investigated the CD4(+) T cell response to the recently identified tumor antigen Midkine (MDK). By weekly stimulations of T lymphocytes harvested from seven HLA-DR-typed healthy donors, we derived CD4(+) T cell lines specific for eight MDK peptides. Most of the T cell lines reacted with the peptides 9-23 and 14-28, located in and overlapping the MDK signal peptide, respectively. Accordingly, the MDK signal peptide appeared to be rich in good binders to common HLA-DR molecules. The peptide 9-23-specific T cell lines were specifically stimulated by autologous dendritic cells loaded with lysates of MDK-transfected cells or with lysates of tumor cells naturally expressing the MDK protein. One T cell line was stimulated by HLA-compatible MDK-transfected tumor cells. By contrast, the peptide 14-28-specific T cell lines were not stimulated in any of these conditions. Our data demonstrate that CD4(+) T cell epitopes present in the signal peptide can be accessible to recognition by CD4(+) T cells and may therefore contribute to tumor immunity, whereas a peptide overlapping the junction between the signal peptide and the mature protein is not.
authors.affiliation: Commissariat à l'Energie Atomique, iBiTecS, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Labex LERMIT, Labex VRI, Gif Sur Yvette F-91191, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Kerzerho
authors.forename: Aurélie
authors.initials: A
authors.lastname: Schneider
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Favry
authors.forename: Florence Anne
authors.initials: FA
authors.lastname: Castelli
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillère
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes; D002478:Cells, Cultured; D016207:Cytokines / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D000078792:Midkine; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D021382:Protein Sorting Signals / Q000502:physiology*
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D010446:Peptide Fragments; D021382:Protein Sorting Signals; D000078792:Midkine
keywords: Antigen Presentation; Epitope Mapping; Immunology; Major Histocompatibility Complex (MHC); T Cell; Tumor Immunology
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