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

tel-00827710, version 1 - 29 May 2013
known to be critical for effective cross-presentation, their disappearance also has
the potential to inhibit cross-priming. Further discussion of this point will be
continued below.
- Although the direct action of type I IFN on T cells has been described previously,
further investigation of that mechanism is needed in our model, as our current
results are inconclusive (Figures 45 and 48). However, preliminary date (not
shown) using in vivo imaging confirms previous results suggesting that poly I:C
treatment induces the retention of T cells in lymphoid organs (Shiow et al., 2006)
(Figure 52, (3)).
- No effects of adjuvant delivery on the injected antigenic cells were observed in our
experiments. Specifically, it does not seem to impact their migration into the
draining lymph nodes. However, it is important to note that the live splenocyte
preparation is theorically sensitive to adjuvant. This potential caveat needs further
investigation.
Some compelling data from previously published studies could be used to complete our
model, especially at the cellular level. In mice, Lorenzi et al. showed that type I IFN did not
affect antigen uptake but induced an increase in the retention of engulfed antigen in
subcellular compartments. This could be due to the regulation of phagosomal pH by type I
IFN (Lorenzi et al., 2011). Interestingly, other intracellular organelles required for cross-
presentation are also modulated by poly I:C treatment, including the lipid bodies that are lipid
storage organelles required for cross-presentation, although we do not yet know in which
process they are involved. In particular, poly I:C promotes the accumulation of lipid bodies,
especially in CD8α + DCs which favors cross-presentation (Bougneres et al., 2009).
Additionally, a study using human DCs treated with type I IFN demonstrated enhanced cross-
presentation due to the promotion of antigen survival as well as directed targeting of the
antigen to the cross-presentation pathway, rather than direct presentation on MHC-II
molecules (Spadaro et al., 2012). Finally the induction of CD8α + DC death by poly I:C
treatment may also contribute to our observations (Fuertes Marraco et al., 2011). All these
studies characterizing effects of type I IFN at the cellular level further support our
observations of the positive effects of adjuvant on cross-priming when administered with the
proper timing. Interestingly, we observed in our model that early adjuvant delivery inhibited
T cell priming but also that substantially delayed delivery (i.e. on day 3 post-immunization
for the i.v. route for instance, data not shown) did not boost the T cell response at all, as
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