TY - JOUR

T1 - Elimination of immunodominant epitopes from multispecific DNA-based vaccines allows induction of CD8 T cells that have a striking antiviral potential

AU - Riedl, Petra

AU - Wieland, Andreas

AU - Lamberth, Kasper

AU - Buus, Søren

AU - Lemonnier, Francois

AU - Reifenberg, Kurt

AU - Reimann, Jörg

AU - Schirmbeck, Reinhold

N1 - Keywords: Animals; Antigens, Polyomavirus Transforming; CD8-Positive T-Lymphocytes; Cell Line; Epitopes, T-Lymphocyte; Female; H-2 Antigens; HSP70 Heat-Shock Proteins; Hepatitis B Core Antigens; Hepatitis B Vaccines; Hepatitis B e Antigens; Hepatitis B virus; Humans; Immunodominant Epitopes; Liver Diseases; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Binding; Protein Structure, Tertiary; Vaccines, DNA; Virus Replication

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.4049/jimmunol.0900505

DO - 10.4049/jimmunol.0900505

M3 - Journal article

C2 - 19542448

VL - 183

SP - 370

EP - 380

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -