Abstract
Immunodominance limits the TCR diversity of specific antiviral CD8 T cell responses elicited by vaccination or infection. To prime multispecific T cell responses, we constructed DNA vaccines that coexpress chimeric, multidomain Ags (with CD8 T cell-defined epitopes of the hepatitis B virus (HBV) surface (S), core (C), and polymerase (Pol) proteins and/or the OVA Ag as stress protein-capturing fusion proteins. Priming of mono- or multispecific, HLA-A*0201- or K(b)-restricted CD8 T cell responses by these DNA vaccines differed. K(b)/OVA(257-264)- and K(b)/S(190-197)-specific CD8 T cell responses did not allow priming of a K(b)/C(93-100)-specific CD8 T cell response in mice immunized with multidomain vaccines. Tolerance to the S- Ag in transgenic Alb/HBs mice (that express large amounts of transgene-encoded S- Ag in the liver) facilitated priming of subdominant, K(b)/C(93-100)-specific CD8 T cell immunity by multidomain Ags. The "weak" (i.e., easily suppressed) K(b)/C(93-100)-specific CD8 T cell response was efficiently elicited by a HBV core Ag-encoding vector in 1.4HBV-S(mut) tg mice (that harbor a replicating HBV genome that produces HBV surface, core, and precore Ag in the liver). K(b)/C(93-100)-specific CD8 T cells accumulated in the liver of vaccinated 1.4HBV-S(mut) transgenic mice where they suppressed HBV replication. Subdominant epitopes in vaccines can hence prime specific CD8 T cell immunity in a tolerogenic milieu that delivers specific antiviral effects to HBV-expressing hepatocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / administration & dosage
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / immunology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Cell Line
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Epitopes, T-Lymphocyte / administration & dosage
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Epitopes, T-Lymphocyte / genetics*
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Epitopes, T-Lymphocyte / metabolism
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Female
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H-2 Antigens / administration & dosage
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H-2 Antigens / genetics
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H-2 Antigens / metabolism
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HSP70 Heat-Shock Proteins / administration & dosage
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / immunology
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HSP70 Heat-Shock Proteins / metabolism
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Hepatitis B Core Antigens / genetics
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Hepatitis B Core Antigens / immunology
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Hepatitis B Core Antigens / metabolism
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Hepatitis B Vaccines / administration & dosage
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Hepatitis B Vaccines / genetics*
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Hepatitis B Vaccines / immunology*
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Hepatitis B e Antigens / genetics
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Hepatitis B e Antigens / immunology
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Hepatitis B e Antigens / metabolism
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Hepatitis B virus / genetics
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Hepatitis B virus / immunology
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Humans
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Immunodominant Epitopes / administration & dosage
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Immunodominant Epitopes / genetics*
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Immunodominant Epitopes / metabolism
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Liver Diseases / immunology
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Liver Diseases / prevention & control
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Liver Diseases / virology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Protein Binding / genetics
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Protein Binding / immunology
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Protein Structure, Tertiary / genetics
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Vaccines, DNA / administration & dosage
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Vaccines, DNA / genetics
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Vaccines, DNA / immunology*
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Virus Replication / genetics
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Virus Replication / immunology*
Substances
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Antigens, Polyomavirus Transforming
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Epitopes, T-Lymphocyte
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H-2 Antigens
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H-2Kb protein, mouse
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HSP70 Heat-Shock Proteins
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Hepatitis B Core Antigens
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Hepatitis B Vaccines
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Hepatitis B e Antigens
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Immunodominant Epitopes
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Vaccines, DNA