Human cytomegalovirus pp65- and immediate early 1 antigen-specific HLA class I-restricted cytotoxic T cell responses induced by cross-presentation of viral antigens.
Dendritic cells (DCs) play a pivotal role in the development of anti-viral CD8(+) CTL responses. This is straightforward if they are directly infected with virus, but is less clear in response to viruses that cannot productively infect DCS: Human CMV (HCMV) shows strain-specific cell tropism: fibroblast (Fb)-adapted laboratory strains (AD169) and recent clinical isolates do not infect DCs, whereas endothelial cell-adapted strains (TB40/E) result in productive lytic DC infection. However, we show here that uninfected DCs induce CD8(+) T cell cytotoxicity and IFN-gamma production against HCMV pp65 and immediate early 1 Ags following in vitro coculture with HCMV-AD169-infected Fbs, regardless of the HLA type of these FBS: CD8(+) T cell stimulation was inhibited by pretreatment of DCs with cytochalasin B or brefeldin A, indicating a phagosome/endosome to cytosol pathway. HCMV-infected Fbs were not apoptotic as measured by annexin V binding, and induction of apoptosis of infected Fbs in vitro did not augment CTL induction by DCs, suggesting a mechanism other than apoptosis in the initiation of cross-presentation. Furthermore, HCMV-infected Fbs provided a maturation signal for immature DCs during coculture, as evidenced by increased CD83 and HLA class II expression. Cross-presentation of HCMV Ags by host DCs enables these professional APCs to bypass some of the evasion mechanisms HCMV has developed to avoid T cell recognition. It may also serve to explain the presence of immediate early 1 Ag-specific CTLs in the face of pp65-induced inhibition of Ag presentation at the level of the infected cell.
Tabi
Z
Z
Department of Medicine, University of Wales, College of Medicine, Cardiff, United Kingdom. tabiz@cf.ac.uk
Moutaftsi
M
M
Borysiewicz
L K
LK
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics; D000956:Antigens, Viral / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D020126:Brefeldin A / Q000494:pharmacology; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D003571:Cytochalasin B / Q000494:pharmacology; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D049452:Green Fluorescent Proteins; D006680:HLA Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014763:Viral Matrix Proteins / Q000276:immunology*; D014764:Viral Proteins
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D008164:Luminescent Proteins; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; C065418:cytomegalovirus matrix protein 65kDa; D049452:Green Fluorescent Proteins; D020126:Brefeldin A; D003571:Cytochalasin B