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

tel-00827710, version 1 - 29 May 2013
III. COMBINATION OF ANTIGEN WITH ADJUVANT
A. The timing of adjuvant delivery should be coordinated with
antigen processing and presentation
1) Effects of poly I:C and type I IFN in our model
Adjuvants and more specifically type I IFN can impact CD8 + T cell cross-priming in a variety
of ways. In our specific model we demonstrated that the optimal timing of adjuvant delivery
is immunization route-dependent (Figure 37). Moreover, for the optimal benefit,
administration should be closely coordinated with the timing of antigen uptake and
presentation, as delivery that occured too early inhibited subsequent priming while late
delivery enhanced it (Figure 38). These effects of poly I:C were shown to be type I IFN-
dependent (Figures 41 and 46). Specifically, we observed that poly I:C and type I IFN act at
several levels. From these results, we propose a model for adjuvant action and timing of
delivery that illustrates how these diverse effects can impact cross-priming, based on the
kinetic of antigen uptake, processing and presentation in both a positive or negative fashion.
Figure 52 recapitulates these points in different experimental conditions: (A) absence of
adjuvant, (B) early adjuvant delivery, (C) late adjuvant delivery.
In our model of immunization with cell-associated antigen, in combination with poly I:C
adjuvant delivery, we observed:
- A substantial recruitment of DCs into the draining lymph node (Figure 43A). If
these cells have already phagocytosed antigen, this recruitment can be considered
to have a positive effect for cross-priming, as it may increase the amount of
antigen reaching the draining lymph node. In contrast, if antigen has not yet been
engulfed, then this flow of DCs to lymph node results in the removal of them from
the skin, rendering them no longer capable of phagocytosing antigen (Figure 52,
(1)).
- In parallel, poly I:C treatment induced DC maturation (Figure 43B). Again, this
process will potentiate cross-priming if the antigen has already been phagocytosed,
by improving the ability of DCs to activate T cells. However, if these maturation
signals arrive before antigen engulfment, DC maturation would lead to
downregulation of antigen capture ability and inhibition of cross-presentation
(Figure 52, (2)).
- We observed the disappearance of CD8α + DCs upon poly I:C stimulation (Figures
43 and 44), which may be due to death of this cell subset. As these cells are
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