Cross-presentation of human cytomegalovirus pp65 (UL83) to CD8+ T cells is regulated by virus-induced, soluble-mediator-dependent maturation of dendritic cells.
Cytotoxic CD8+ T lymphocytes (CTL) directed against the matrix protein pp65 are major effectors in controlling infection against human cytomegalovirus (HCMV), a persistent virus of the Betaherpesvirus family. We previously suggested that cross-presentation of pp65 by nonpermissive dendritic cells (DCs) could overcome viral strategies that interfere with activation of CTL (G. Arrode, C. Boccaccio, J. Lule, S. Allart, N. Moinard, J. Abastado, A. Alam, and C. Davrinche, J. Virol. 74:10018-10024, 2000). It is well established that mature DCs are very potent in initiating T-cell-mediated immunity. Consequently, the DC maturation process is a key step targeted by viruses in order to avoid an immune response. Here, we report that immature DCs maintained in coculture with infected human (MRC5) fibroblasts acquired pp65 from early-infected cells for cross-presentation to specific HLA-A2-restricted CTL. In contrast, coculture of DCs in the presence of late-infected cells decreased their capacity to stimulate CTL. Analyses of DC maturation after either coculture with infected MRC5 cells or incubation with infected-cell-conditioned medium revealed that acquisition of a mature phenotype was a prerequisite for efficient stimulation of CTL and that soluble factors secreted by infected cells were responsible for both up and down regulation of CD83 expression on DCs. We identified transforming growth factor beta1 secreted by late HCMV-infected cells as one of these down regulating mediators. These findings suggest that HCMV has devised another means to compromise immune surveillance mechanisms. Together, our data indicate that recognition of HCMV-infected cells by DCs has to occur early after infection to avoid immune evasion and to allow generation of anti-HCMV CTL.
Arrode
Géraldine
G
INSERM U395, IFR 30, UPS, CNRS, CHU, 31024 Toulouse Cédex, France.
Boccaccio
Claire
C
Abastado
Jean-Pierre
JP
Davrinche
Christian
C
D017951:Antigen Presentation; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D003587:Cytomegalovirus / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000276:immunology; D008562:Membrane Glycoproteins; D010750:Phosphoproteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic; D013997:Time Factors; D014763:Viral Matrix Proteins / Q000276:immunology*; D000097802:CD83 Antigen
D015703:Antigens, CD; D017077:Culture Media, Conditioned; D015789:HLA-A2 Antigen; D007136:Immunoglobulins; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; D000097802:CD83 Antigen; C065418:cytomegalovirus matrix protein 65kDa