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

tel-00827710, version 1 - 29 May 2013
itself to initiate the response. DCs must sense the PAMPs directly. This initially seems in
contradiction with previous work showing that cytokines such as IL-12 or type I IFN could be
sufficient (Curtsinger and Mescher, 2010). It is possible that a PAMP contamination of the
cytokines used in the previous studies could explain this difference. The requirement for
direct PAMP detection allows the DC to evaluate the nature of the agent causing the
inflammation in order to modulate an appropriate response. It is also possible that other kinds
of signals such as some DAMPs have the same ability to activate DCs to initiate an immune
response. DCs that have matured by bystander signals but are not fully activated may have a
regulatory role in the immune response (Joffre et al., 2009). While inflammation by itself
does not appear sufficient to initiate the response, it is important to note that inflammatory
cytokines produced by bystander cells are required in some cases to promote efficient
priming. For instance, Longhi and colleagues demonstrated that type I IFN production from
stromal and hematopoietic origin are required for the priming of CD4 + T cells (Longhi et al.,
2009).
(ii) Requirement for detection of antigen and TLR ligand
in the same phagosome
Blander and Medzhitov went further and proposed a model to distinguish self from non-self at
the subcellular level of phagosome through TLR engagement (Blander and Medzhitov, 2006).
Indeed phagocytosis is critical for two different, but related mechanisms: (i) the removal of
apoptotic cells to maintain tissue homeostasis, a process that must be done without inducing
any inflammatory response; and (ii) the engulfment of pathogens, a function in host defense
that will be associated with stimulating an immune response. Blander et al. have demonstrated
that in macrophages, TLR ligands must be associated with antigen and internalized in the
same phagosome to trigger antigen processing and presentation on MHC-II molecule
(Blander and Medzhitov, 2004). By contrast, apoptotic cells are also phagocytosed but are not
associated with TLR ligand engagement and thus, a tolerogenic response and degradation of
this cargo is induced. They suggested that TLR signaling induces a different phagosomal
maturation pathway with an enhanced kinetic and the generation of MHC-II molecules ready
to present antigen. These results remain controversial, as another group has demonstrated that
phagosome maturation occurs independently of TLR signaling (Yates and Russell, 2005).
4) What happens when a signal is missing? Tolerance vs priming
It was initially proposed that signal 1 alone induces tolerance while the addition of signal 2
provides for DC maturation and, therefore allows T cell priming (Steinman and Nussenzweig,
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