title: Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T-cell activation.
abstract: Protective T-cell responses depend on efficient presentation of antigen (Ag) in the context of major histocompatibility complex class I (MHCI) and class II (MHCII) molecules. Invariant chain (Ii) serves as a chaperone for MHCII molecules and mediates trafficking to the endosomal pathway. The genetic exchange of the class II-associated Ii peptide (CLIP) with antigenic peptides has proven efficient for loading of MHCII and activation of specific CD4(+) T cells. Here, we investigated if Ii could similarly activate human CD8(+) T cells when used as a vehicle for cytotoxic T-cell (CTL) epitopes. The results show that wild type Ii, and Ii in which CLIP was replaced by known CTL epitopes from the cancer targets MART-1 or CD20, coprecipitated with HLA-A*02:01 and mediated colocalization in the endosomal pathway. Furthermore, HLA-A*02:01-positive cells expressing CLIP-replaced Ii efficiently activated Ag-specific CD8(+) T cells in a TAP- and proteasome-independent manner. Finally, dendritic cells transfected with mRNA encoding IiMART-1 or IiCD20 primed naïve CD8(+) T cells. The results show that Ii carrying antigenic peptides in the CLIP region can promote efficient presentation of the epitopes to CTLs independently of the classical MHCI peptide loading machinery, facilitating novel vaccination strategies against cancer.
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Oslo, Norway.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.forename: Shraddha
authors.initials: S
authors.lastname: Kumari
authors.forename: Lars-Egil
authors.initials: LE
authors.lastname: Fallang
authors.forename: Kine M K
authors.initials: KM
authors.lastname: Sand
authors.forename: Weiwen
authors.initials: W
authors.lastname: Yang
authors.forename: Ole J B
authors.initials: OJ
authors.lastname: Landsverk
authors.forename: Oddmund
authors.initials: O
authors.lastname: Bakke
authors.forename: Johanna
authors.initials: J
authors.lastname: Olweus
authors.forename: Tone F
authors.initials: TF
authors.lastname: Gregers
mesh_terms: D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000941:Antigens; D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010455:Peptides; C045084:invariant chain; D046988:Proteasome Endopeptidase Complex
keywords: Antigen presentation/processing; CD8+ T cells; MHC; Vaccination