title: Single chain MHC I trimer-based DNA vaccines for protection against Listeria monocytogenes infection.
abstract: To circumvent limitations of poor antigen presentation and immunogenicity of DNA vaccines that target induction of CD8(+) T cell immunity, we have generated single chain MHC I trimers (MHC I SCTs) composed of a single polypeptide chain with a linear composition of antigenic peptide, β2-microglobulin, and heavy chain of a MHC class I molecule connected by flexible linkers. Because of its pre-assembled nature, the SCT presents enhanced expression and presentation of the antigenic peptide/MHC complexes at the cell surface. Furthermore, DNA vaccination with a plasmid DNA encoding an SCT incorporating an immunodominant viral epitope elicited protective CD8(+) T cell responses against lethal virus infection. To extend these findings, here we tested the efficacy of SCT DNA vaccines against bacterial infections. In a mouse infection model of Listeria monocytogenes, the SCT DNA vaccine encoding H-2K(d) and the immunodominant peptide LLO 91-99 generated functional primary and memory peptide-specific CD8(+) T cells that confer partial protection against L. monocytogenes infection. DNA immunization of K(d)/LLO(91-99) SCTs generated functional memory CD8(+) T cells independently of CD4(+) T cells, although the expression of cognate or non-cognate CD4(+) helper T cell epitopes further enhanced the protective efficacy of SCTs. Our study further demonstrates that the SCT serves as a potent platform for DNA vaccines against various infectious diseases.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Sojung
authors.initials: S
authors.lastname: Kim
authors.forename: Adam
authors.initials: A
authors.lastname: Zuiani
authors.forename: Javier A
authors.initials: JA
authors.lastname: Carrero
authors.forename: Ted H
authors.initials: TH
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000032:analysis; D058491:Bacterial Load; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control*; D008099:Liver / Q000382:microbiology; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D001613:beta 2-Microglobulin; D007371:Interferon-gamma