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

tel-00827710, version 1 - 29 May 2013
2002). However it has been observed that mature DCs are not always sufficient to prime T
cells (Albert et al., 2001; Fujii et al., 2004). The critical checkpoint between tolerance and
priming seems to be the presence of a signal 3. In vitro experiments with artificial APCs
demonstrated that antigen and costimulation signals trigger T cell expansion but without
effector function and memory development. In this case, the T cells that persist are tolerant. In
contrast, if a third signal is provided, T cell expansion is accompanied by complete effector
function development and memory T cell differentiation (Curtsinger et al., 1999). This has
been confirmed by in vivo experiment with peptide immunization. Injection of peptide alone
triggers tolerance, whereas it is capable of inducing T cell priming when delivered in
combination with IL-12, playing the role of adjuvant and providing the third signal (Schmidt
and Mescher, 1999).
5) Other factors regulating T cell activation
This model with 3 signals required for the proper induction of a T cell response represents the
established scientific dogma. In addition, several other factors and signals have been
described that further modulate this process.
(a) Antigen persistence
CD4 + and CD8 + T cells are both able to proliferate even after a short antigenic stimulation.
However, these two populations seem not to require the same duration of antigenic
stimulation for optimal priming.
It has been demonstrated that CD4 + T cells need a long antigenic stimulation for optimal
priming and differentiation. Short exposure to antigen allows for low-level proliferation of
CD4 + T cells but a longer stimulation increases this proliferation. These cells stop
proliferating as soon as the antigen dose decreases under a certain threshold. Moreover,
continuous stimulation throughout the expansion phase is required for the optimal
differentiation (Obst et al., 2005).
By contrast, CD8 + T cells can completely differentiate even after a very short interaction with
APCs. In vitro, CD8 + T cells stimulated for only a short period of time can proliferate (van
Stipdonk et al., 2001). In a model of infection by Listeria monocytogenes, it has been
demonstrated that CD8 + T cells can proliferate in spite of the removal of bacteria after the use
of antibiotic (Mercado et al., 2000). Bevan and Fink proposed an “autopilot” model for the
development of CD8 + T cells, meaning that a CD8-specific transcriptional program is
engaged after the initial antigen encounter and that differentiation occurs even in the absence
of sustained antigen stimulation (Bevan and Fink, 2001). However this model has been
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