Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens.
The presentation of antigenic peptides by major histocompatibility complex (MHC) class II molecules to CD4+ T cells is critical to the function of the immune system. In this study, we have utilized the sorting signal of the lysosomal-associated membrane protein LAMP-1 to target a model antigen, human papillomavirus 16 E7 (HPV-16 E7), into the endosomal and lysosomal compartments. The LAMP-1 sorting signal reroutes the antigen into the MHC class II processing pathway, resulting in enhanced presentation to CD4+ cells in vitro. In vivo immunization experiments in mice demonstrated that vaccinia containing the chimeric E7/LAMP-1 gene generated greater E7-specific lymphoproliferative activity, antibody titers, and cytotoxic T-lymphocyte activities than vaccinia containing the wild-type HPV-16 E7 gene. These results suggest that specific targeting of an antigen to the endosomal and lysosomal compartments enhances MHC class II presentation and vaccine potency.
Wu
T C
TC
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Guarnieri
F G
FG
Staveley-O'Carroll
K F
KF
Viscidi
R P
RP
Levitsky
H I
HI
Hedrick
L
L
Cho
K R
KR
August
J T
JT
Pardoll
D M
DM
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002451:Cell Compartmentation; D003602:Cytotoxicity, Immunologic; D005802:Genes, MHC Class II; D008213:Lymphocyte Activation; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D015202:Protein Engineering; D021382:Protein Sorting Signals / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology
D015703:Antigens, CD; D015704:CD4 Antigens; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16