Elimination of immunodominant epitopes from multispecific DNA-based vaccines allows induction of CD8 T cells that have a striking antiviral potential.
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.
Riedl
Petra
P
Department of Internal Medicine I, University of Ulm, Germany.
Wieland
Andreas
A
Lamberth
Kasper
K
Buus
Soren
S
Lemonnier
Francois
F
Reifenberg
Kurt
K
Reimann
Jörg
J
Schirmbeck
Reinhold
R
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006183:H-2 Antigens / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D008107:Liver Diseases / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
D000952:Antigens, Polyomavirus Transforming; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D018840:HSP70 Heat-Shock Proteins; D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens; D016056:Immunodominant Epitopes; D019444:Vaccines, DNA