Dendritic cell-induced apoptosis of human cytomegalovirus-infected fibroblasts promotes cross-presentation of pp65 to CD8+ T cells.
An efficient host response to human cytomegalovirus (HCMV) infection may depend on rapid sensing of the infection by the innate immune response prior to deployment of viral immunosubversive functions. Control of HCMV dissemination could be ensured by apoptosis of cells immediately following infection. In the present report, it is demonstrated that changes in the ratio of c-FLIP to FLICE contributed to early sensitivity of HCMV-infected MRC5 fibroblasts to tumour necrosis factor alpha (TNF-alpha), providing an innate response to infection. Dendritic cells (DCs) co-cultured with HCMV-infected MRC5 cells acquired the ability to secrete TNF-alpha in an amount sufficient to kill infected fibroblasts. Blockage of TNF-alpha binding to its receptor on MRC5 cells with soluble TNF-R reduced the number of dead, HCMV-infected fibroblasts ingested by DCs, thus highlighting the impact of the apoptotic state of infected cells for efficient loading of DCs. Those DCs loaded with antigens available early in infection, such as input virion-associated pp65, could then engage antigen processing for cross-presentation to specific CD8(+) T cells. Cross-presentation was impaired when MRC5 cells were treated with the pan-caspase inhibitor ZVAD before co-culture with DCs. Altogether, our data suggest that the innate killing capacity of DCs at the early stage of infection plays a role in the activation of anti-HCMV CD8(+) T cells.
Mandron
Marie
M
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France.
Martin
Hélène
H
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France.
Bonjean
Béatrice
B
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France.
Lulé
Jacqueline
J
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France.
Tartour
Eric
E
EA4054, Université René Descartes-Paris 5, Paris, France.|Laboratoire d'Immunologie, Hôpital Européen Georges Pompidou, Paris, France.
Davrinche
Christian
C
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France.
D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics*
D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa