Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
(b) Effects of type I IFN on dendritic cells
(i) DC lifespan
Regulated apoptosis of DCs controls the magnitude of an immune response by limiting
antigen presentation to specific T cells and is modulated by both extrinsic and T-cell mediated
signals (Kushwah and Hu, 2010). Under steady state conditions, immature DCs express high
levels of the anti-apoptotic molecule Bcl-2 and their half-life is approximately 1.5 to 3 days.
Upon activation, DCs downregulate Bcl-2 expression allowing for increased apoptosis and
eventually leading to their terminal differentiation and death. Type I IFN are capable of
regulating DC turnover in vivo. DC turnover is more rapid in WT than in IFNAR -/- mice and
injection of a type I IFN inducer enhances the turnover of DCs in WT mice further (Mattei et
al., 2009). Specifically, it was recently demonstrated that poly I:C injection induces transient
DC activation followed by a marked reduction in the number of CD8α + cDCs due to the
apoptotic cell death (Fuertes Marraco et al., 2011). To distinguish whether this decrease was
due to DC migration or death, they sorted DCs a few hours post-injection and examined the
induction of apoptosis. They demonstrated that poly I:C modulates the expression of pro- and
anti-apoptotic genes and that these differential patterns are dependent on type I IFN signaling.
In fact, the initiation of apoptosis is not specific for poly I:C, as the same effect was observed
upon treatment with other adjuvants. A caveat to this work is that it was performed following
the injection of a TLR ligand known to induce IFN only – without the administration of
antigen. Interestingly, in a model combining administration of cell-associated antigen with
type I IFN, it was shown that type I IFN sustain the survival of antigen-bearing DCs whereas
it induces the apoptosis of bystander DCs by regulating pro- and anti-apoptotic genes
(Lorenzi et al., 2011).
(ii) DC maturation
Following type I IFN administration, mouse cDCs undergo both a phenotypic and functional
maturation upon type I IFN exposure (Montoya et al., 2002). Moreover, type I IFN appear to
participate in increasing the efficiency of cross-priming of CD8 + T cells. Le Bon and
colleagues showed this phenomena was due to a direct action of type I IFN on the DCs by
comparing cross-priming ability of WT versus IFNAR -/- DCs (Le Bon et al., 2003).
Furthermore, these cytokines allow a higher amount of peptide-MHC-I complexes and
maturation markers on the DC surface (Lorenzi et al., 2011).
Similarly, immature human cDCs treated with type I IFN upregulate MHC, as well as
costimulatory molecules and have been shown to be better inducers of effective CD8 + T cell
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