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As immature DCs progress to an early activated state, gene expression is
characterized by induction of genes involved in antigen processing and cytoskeletal
rearrangements and downregulation of genes involved in pathogen recognition and
phagocytosis. In addition, the transcription of proinflammatory genes such as TNFα
and IL-1 is induced. Within a few hours the early “activated” DC progresses to a
second “transitional” gene expression program consisting of the induction of many
chemokines, transcription factors, and components of intracellular signaling
pathways. Finally, by 18 hours following antigen exposure, DCs display a “mature”
transcriptional program characterized by the induction of genes involved in apoptosis
regulation, intercellular signaling and T-cell stimulation. These time-dependent
classes of gene expression correspond broadly to known DC functions over time.
Initially DCs are involved in pathogen phagocytosis. Following pathogen exposure,
however, DCs rapidly influence the local innate immune response, producing
cytokines that affect macrophage, natural killer cell, and neutrophil function. Finally,
as discussed, DCs in local lymphoid tissue interact and stimulate T and B cells
requiring the transcriptional induction of specific functions.
7.3.2 Plasticity in Dendritic Cell Transcriptional Programs
Given that dendritic cells can direct different outcomes at the level of T-cell
polarization they must therefore interpret and translate different antigenic input
stimuli to instruct these outcomes. As we have seen, two nonexclusive theories
predict that different DC subsets produce differential outcomes to a given pathogen
(2.1.1), or a given DC is flexible in its response. Transcriptional profiling of DCs
exposed to different pathogens and PAMPs clearly shows the induction of different
gene sets superimposed over the “core” DC maturation program (Huang et al. 2001;
Granucci et al. 2001a; Granucci et al. 2001b; Kwan and Kellam, unpublished
observations). The first study comparing bacterial, viral, and yeast exposure to DCs
(Huang et al. 2001) showed that the bacterium, E. coli specifically induced the
expression of 118 genes. These included the rapid activation of a potent
inflammatory response and the later induction of T-cell stimulating genes including a
subset of chemokines thought to attract naïve T H 2 T helper cells. In contrast,
influenza virus strongly induced antiviral genes including type 1 interferons and
interferon-inducible chemokines, although the induction of these genes may simply
reflect the ability of influenza to replicate in DCs (Huang et al. 2001). A related
study comparing LPS and TNFα stimulation of DCs showed very different patterns
of DC gene expression but importantly identified the TNFα stimulus as providing
only a “mild alert” effect compared to LPS which stimulates full DC maturation
(Granucci et al. 2001a). These studies highlight the importance of the stimulatory
context of different pathogens, but clearly highlight DC transcriptional plasticity to
diverse pathogens, although care should be taken in such studies as different LPS
preparations can have variable effects on DCs.
Using similar approaches we have determined that DCs can transcriptionally
distinguish between two RNA genome viruses, human rhinovirus and influenza
virus, which differ by the presence of a viral lipid envelope and the type of RNA
genome. In addition, DCs can discriminate between replication-competent and
inactivated viruses (Fig. 3).
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