Direct priming and cross-priming contribute differentially to the induction of CD8+ CTL following exposure to vaccinia virus via different routes.
To explore the relative importance of direct presentation vs cross-priming in the induction of CTL responses to viruses and viral vectors, we generated a recombinant vaccinia vector, vUS11, expressing the human CMV (HCMV) protein US11. US11 dislocates most allelic forms of human and murine MHC class I heavy chains from the lumen of the endoplasmic reticulum into the cytosol, where they are degraded by proteasomes. Expression of US11 dramatically decreased the presentation of viral Ag and CTL recognition of infected cells in vitro without significantly reducing total cell surface MHC class I levels. However, because US11 is an endoplasmic reticulum resident membrane protein, it cannot block presentation by non-infected cells that take up Ag through the cross-priming pathway. We show that the expression of US11 strongly inhibits the induction of primary CD8(+) CTLs when the infection occurs via the i.p. or i.v. route, demonstrating that direct priming is critical for the induction of CTL responses to viral infections introduced via these routes. This effect is less dramatic following i.m. infection and is minimal after s.c. or intradermal infection. Thus, classic MHC class I Ag presentation and cross-priming contribute differentially to the induction of CD8(+) CTLs following exposure to vaccinia virus via different routes.
Shen
Xuefei
X
Program in Biochemistry, Department of Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Wong
S B Justin
SB
Buck
Christopher B
CB
Zhang
Jiangwen
J
Siliciano
Robert F
RF
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007271:Injections, Intradermal; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D014407:Tumor Cells, Cultured; D014611:Vaccination / Q000379:methods*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014765:Viral Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology*
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; D014614:Vaccines, Synthetic; D014764:Viral Proteins; D014765:Viral Vaccines