title: IFN-α boosts epitope cross-presentation by dendritic cells via modulation of proteasome activity.
abstract: We have investigated the molecular mechanisms underlying the peculiar cross-presentation efficiency of human dendritic cells (DCs) differentiated from monocytes in the presence of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Interferon (IFN)-α (IFN-DCs). To this end, we evaluated the capability of IFN-DCs to present and cross-present epitopes derived from Epstein-Barr Virus (EBV) or human melanoma-associated antigens after exposure to cell lysates or apoptotic cells. In an autologous setting, IFN-DCs loaded with Lymphoblastoid Cell Lines (LCL) lysates or apoptotic LCL were highly efficient in expanding, respectively, EBV-specific class II- or class I-restricted memory T cell responses. Of note, IFN-DCs loaded with apoptotic LCL were more potent than fully mature DCs in triggering the cytotoxicity of CD8(+) T lymphocytes recognizing a subdominant HLA-A*0201-restricted epitope derived from EBV latent membrane protein 2 (LMP2). In addition, IFN-DCs loaded with apoptotic human melanoma cells were highly efficient in cross-presenting the MART-1(27-35) epitope to a specific CD8(+) cytotoxic T cell clone, and this functional activity was proteasome-dependent. These IFN-DC properties were associated with an enhanced expression of all the immunoproteasome subunits as well as of TAP-1, TAP-2 and tapasin, and, interestingly, to a higher proteasome proteolytic activity as compared to immature or mature DCs. Altogether, these results highlight new mechanisms by which IFN-α influences antigen processing and cross-presentation ability of monocyte-derived DCs, with potentially important implications for the development of DC-based therapeutic vaccines.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzi
authors.forename: Carmela
authors.initials: C
authors.lastname: Rozera
authors.forename: Diego
authors.initials: D
authors.lastname: Marescotti
authors.forename: Giuseppina
authors.initials: G
authors.lastname: D'Agostino
authors.forename: Laura
authors.initials: L
authors.lastname: Santodonato
authors.forename: Silvia
authors.initials: S
authors.lastname: Cellini
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Gavioli
authors.forename: Maria
authors.initials: M
authors.lastname: Ferrantini
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D045142:Cross-Priming; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D009363:Neoplasm Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016898:Interferon-alpha; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; D014763:Viral Matrix Proteins; D046988:Proteasome Endopeptidase Complex