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.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
T C
TC
Wu
F G
FG
Guarnieri
K F
KF
Staveley-O'Carroll
R P
RP
Viscidi
H I
HI
Levitsky
L
L
Hedrick
K R
KR
Cho
J T
JT
August
D M
DM
Pardoll
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