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

tel-00827710, version 1 - 29 May 2013
Some synthetic compounds such as imidazoquinolines and adenosine and guanosine analogs,
first developed as type I IFN inducers are known to act as ligands for TLR7 and TLR8
(Hemmi et al., 2002). Although they bind similar ligands, TLR7/8 are differentially expressed
in vivo: TLR7 is found in B cells, neutrophils and pDCs in both human and mice, and also in
macrophages and CD8α − DC in mice; TLR8 is expressed in DCs in human but does not seem
functional in mice (Iwasaki and Medzhitov, 2010). Use of TLR7 and TLR8 ligands has been
demonstrated to activate DCs and pDCs by upregulating costimulatory molecules and
inducing the production of type I IFN and IL-12.
(d) TLR9 ligands
TLR9 is also found in the endosome and is capable of recognizing DNA, preferentially
modified by the CpG dinucleotide (Blasius and Beutler, 2010). Synthetic 18-25
oligodeoxynucleotides with CpG motifs have been developed commercially as an adjuvant
and have been tested as either a soluble molecule or formulated as nanoparticles. TLR9 has a
much more restricted expression profile than the other PRRs previously discussed: it is only
expressed in pDCs and in B cells in humans and mice, and also seen in cDCs in mice only
(Campbell et al., 2009). CpG has been shown to both enhance humoral immunity and favor
Th1 response. CpG primarily activates pDCs. Their stimulation usually results in the release
of large amounts of type I IFN, as pDCs are understood to be “professional” producers of
these cytokines.
3) Signaling pathways implicated in type I IFN production
Several signaling pathways are responsible for the production of type I IFN depending on the
receptor that has been engaged. While ligation of TLR3 and TLR4 ligands triggers a TRIF-
dependent pathway, other molecules such as TLR9 ligands induce a Myd88-dependent
pathway. In most cells, activation of either of these pathways leads to the phosphorylation of
the transcription factor IRF3 that will interact with other molecules to form the
enhanceosome. The enhanceosome then promotes the expression of IFNβ and IFNα4 is then
induced. Secreted type I IFN can participate in an autocrine amplification loop through
IFNAR signaling. Type I IFN bind their receptor inducing the phosphorylation of IRF7,
which stimulates further type I IFN production (Figure 10). Interestingly, the mechanism of
type I IFN production in pDCs is slightly different. They constitutively express IRF7, thus
any inflammatory stimuli directly triggers IRF7 phosphorylation and rapid regulation of type
I IFN production without the requirement for an amplification loop (Honda et al., 2006).
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