Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infectedfibroblasts is cross-presented to CD8(+) T cells by dendritic cells

Human cytomegalovirus (HCMV) infection is well controlled mainly by cytotox ic CD8(+) T lymphocytes (CTL) directed against the matrix protein pp65 desp ite the numerous immune escape mechanisms developed by the virus. Dendritic cells (DCs) are key antigen-presenting cells for the generation of an immu ne response which have the capacity to acquire antigens via endocytosis of apoptotic cells and thus present peptides to major histocompatibility compl ex class I-restricted T cells. We examined whether this mechanism could con tribute to the activation of anti-pp65 CTL, In this study, we show that inf ection by HCMV AD169 induced sensitization of MRC5 fibroblasts to tumor nec rosis factor alpha-mediated apoptosis very early after virus inoculation an d that pp65 contained in apoptotic cells came from the delivery of the matr ix protein into the cell. We observed that immature DCs derived from periph eral monocytes were not permissive to HCMV AD169 infection but were able to internalize pp65-positive apoptotic infected MRC5 cells. We then demonstra ted that following exposure to these apoptotic bodies, DCs could activate H LA-A2- or HLA-B35-restricted anti-pp65 CTL, suggesting that they acquired a nd processed properly fibroblast-derived pp65. Together, our data suggest t hat cross-presentation of incoming pp65 contained in apoptotic cells may pr ovide a quick and efficient way to prime anti-HCMV CD8(+) T cells.