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

tel-00827710, version 1 - 29 May 2013
several different environmental conditions appear to play a large role in modulating the action
of type I IFN.
(i) Type I IFN dose
Differential effects of type I IFN have been described to correlate with the dosing amount.
High levels of type I IFN, such as those produced during viral infections, inhibit IL-12
secretion by DCs whereas lower levels are required for the production of the bioactive IL-12
heterodimer (Gautier et al., 2005). To explain these results, the following model was
proposed: the level of IFN produced corresponds to the severity of the infection and thus, is
capable of modulating the outcome of the response including the induction of differential
mechanisms/functions necessary to combat a wide range of pathogens (Biron, 2001).
(ii) Location of type I IFN secretion
While pDCs are known for their ability to secrete high amounts of type I IFN, every cell of
the body is capable of generating type I IFN upon stimulation. Moreover, each cell type
expresses a specific panel of PRRs and, based on this profile, are more or less responsive to
signals that result in type I IFN production. As previously described, inflammatory signals
derived from hematopoietic or stromal cells are not functionally equivalent. This could be the
case for type I IFN. Stromal production of type I IFN has been shown to be critical in the
control of some infections (Schilte et al., 2010), whereas other immune responses are solely
dependent on IFN production by pDCs.
(iii) Timing of type I IFN production and the activation
state of target cells
Previous studies performed in our lab have demonstrated that IFNα/β has mutually exclusive
effects on human DCs depending on their maturation state. Immature DCs exposed to
IFNα/β were impaired in their ability to cross-present antigen and activate CD8 + T cells,
whereas IFNα/β stimulation of mature DCs results in enhanced T cell activation. The
contradictory actions of type I IFN in this example appear to depend on the timing of
stimulation as compared to the state of DC maturation (Longman et al., 2007). It has been
shown that these differential effects are due to a molecular switch between the use of STAT1
and STAT4 in the IFNAR signaling pathway. These results are in line with a previous study
showing that adjuvant delivery prior to immunization impairs subsequent priming, perhaps
due to the modulation of APC maturation state by the adjuvant (Wilson et al., 2006). Nagai
and colleagues also showed opposite effects of type I IFN on DCs and T helper cell
differentiation that was dependent on the timing of IFN administration. The presence of IFN
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