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

tel-00827710, version 1 - 29 May 2013
antigen is not viewed by the immune system as this dangerous and clearance is less urgent.
For instance, monocytes from the blood respond vigorously to LPS alone in circulation, even
in the absence of other signals. Inversely, tissue-resident macrophages activate the
inflammasome pathway only following the detection of multiple signals of an active
infection, only one of which is the presence of LPS (Blander and Sander, 2012). The same
perspective can be considered in our model for the injected splenocytes (Figure 51, (4)). Cell-
associated antigen might be removed rapidly upon i.v. immunization by macrophages,
explaining the reduced persistence of antigen and less efficient cross-priming: antigen was
removed quickly, so the T cell response does not need to be maintained. However, following
i.d. immunization, local immune cells are less efficient at clearing the injected antigen
because the level of threat is lower; the antigen persists and there remains continual
stimulation to maintain T cell activation and differentiation.
Each of these points highlights potential differences between the mechanims and the context
of intradermal versus intravenous immunization and could be responsible for the differential
outcomes observed for CD8 + T cell response.
3) A role for antigen persistence?
In our model we observed that cross-presentation persisted longer in the draining lymph node
after i.d. immunization that what was seen following i.v. immunization (Figure 32). This
persistence alone could explain the enhanced polyfunctional T cell response (Figure 25), as
well as a more robust secondary T cell response (Figure 26).
As described previously, the requirement for antigen persistence for the generation of an
efficient CD8 + T cell response is quite controversial. It has been initially shown in both an in
vitro model (van Stipdonk et al., 2001) or an in vivo model, in which antigen was removed by
antibiotics (Mercado et al., 2000), that a brief antigenic stimulation is sufficient to trigger a
cell autonomous program of CD8 + T differentiation. However, since the proposal of this
“autopilot model” by Bevan and Fink, highlighting that CD8 + T cells require only a short
stimulation for a complete differentiation, other studies have further defined the model.
Usharauli and colleagues demonstrated in vitro that duration of antigen stimulation matters:
brief antigen stimulation induced the generation of effector CD8 + T cells with low
cytotoxicity and high IL-2 production, whereas a sustained stimulation generated effector
cells with the opposite phenotype that convert quickly into memory-like CD8 + T cells
(Usharauli and Kamala, 2008). In another study, Prlic et al. controlled antigen persistence in
vivo by using CD11c-DTR mice and by removing CD11c + cells via diphteria toxin injection.
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