Enhanced priming of multispecific, murine CD8+ T cell responses by DNA vaccines expressing stress protein-binding polytope peptides.
A polytope DNA vaccine (pCI/pt10) was used that encodes within a 106-residue sequence 10-well characterized epitopes binding MHC class I molecules encoded by the K, D, or L locus (of H-2(d), H-2(b), and H-2(k) haplotype mice). The pCI/pt10 DNA vaccine efficiently primed all four K(b)/D(b)-restricted CD8(+) T cell responses in H-2(b) mice, but was deficient in stimulating most CD8(+) T cell responses in H-2(d) mice. Comparing CD8(+) T cell responses elicited with the pCI/pt10 DNA vaccine in L(d+) BALB/c and L(d-) BALB/c(dm2) (dm2) mice revealed that L(d)-restricted CD8(+) T cell responses down-regulated copriming of CD8(+) T cell responses to other epitopes regardless of their restriction or epitope specificity. Although the pt10 vaccine could thus efficiently co prime multispecific CD8(+) T cell responses, this priming was impaired by copriming L(d)-restricted CD8(+) T cell responses. When the pt10 sequence was fused to a 77-residue DnaJ-homologous, heat shock protein 73-binding domain (to generate a 183-residue cT(77)-pt10 fusion protein), expression and immunogenicity (for CD8(+) T cells) of the chimeric Ag were greatly enhanced. Furthermore, priming of multispecific CD8(+) T cell responses was readily elicited even under conditions in which the suppressive, L(d)-dependent immunodominance operated. The expression of polytope vaccines as chimeric peptides that endogenously capture stress proteins during in situ production thus facilitates copriming of CD8(+) T cell populations with a diverse repertoire.
Schirmbeck
Reinhold
R
Institute of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany.
Fissolo
Nicolas
N
Chaplin
Paul
P
Reimann
Jörg
J
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002645:Chickens; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D006183:H-2 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D064532:Histocompatibility Antigen H-2D; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D064532:Histocompatibility Antigen H-2D; C494372:Hspa8 protein, mouse; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA