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Department of Medicine, University of Wales, College of Medicine, Cardiff, United Kingdom
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-
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.
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