title: Forced expression of HLA-DM at the surface of dendritic cells increases loading of synthetic peptides on MHC class II molecules and modulates T cell responses.
abstract: Adoptive transfer of autologous dendritic cells (DCs) loaded with tumor-associated CD4 and CD8 T cell epitopes represents a promising avenue for the immunotherapy of cancer. In an effort to increase the loading of therapeutic synthetic peptides on MHC II molecules, we used a mutant of HLA-DM (DMY) devoid of its lysosomal sorting motif and that accumulates at the cell surface. Transfection of DMY into HLA-DR(+) cells resulted in increased loading of the exogenously supplied HA(307-318) peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL(48-61) and of the tumor Ag-derived gp100(174-190) peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY(-) and DMY(+) mouse APCs differentially stimulated T cell hybridomas sensitive to the fine conformation of peptide-MHC II complexes. Taken together, our results suggest that the overexpression of HLA-DMY at the plasma membrane of DCs may improve quantitatively, but also qualitatively, the presentation of CD4 T cell epitopes in cellular vaccine therapies for cancer.
authors.affiliation: Laboratoire d'Immunologie Moléculaire, Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
authors.forename: Abdul Mohammad
authors.initials: AM
authors.lastname: Pezeshki
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Côté
authors.forename: Georges A
authors.initials: GA
authors.lastname: Azar
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Mohamed-Rachid
authors.initials: MR
authors.lastname: Boulassel
authors.forename: Jacques
authors.initials: J
authors.lastname: Thibodeau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D057809:HEK293 Cells; D006681:HLA-D Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008247:Lysosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000235:genetics* / Q000276:immunology; D021382:Protein Sorting Signals / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D010455:Peptides; D021382:Protein Sorting Signals