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analog of viral dsRNA, is mainly sensed by TLR3, increases systemic levels
of IFN-I, activates DCs, and boosts antigen-specific CD4
+
T cells
[30]
. More
importantly, TLR3 has been shown to be critical for induction of cross-
presentation of antigens and CD8
+
T-cell responses
[23]
. For the elicitation
of CD8
+
T-cell responses to cross-presentation of dsRNA antigens, TLR3
expression in CD8α
+
DCs has been demonstrated to be critical
[23]
. Further-
more, the TRIF and IFN-promoter stimulator 1 (IPS-1) signaling pathways
are important for boosting CD8
+
T-cell responses. TLR3 has been suggested
to be relevant for enhancing B-cell responses under certain experimental
conditions as well
[31]
. In addition to viral dsRNA, data have demonstrated
that sensing of dsRNA is critical for induction of type 1 diabetes
[32]
. These
data suggest that in addition to recognition of viral dsRNA, TLR3 also might
play a role in the recognition of endogenously derived dsRNA that causes
autoimmunity
[32]
. Another important function of viral dsRNA-mediated
TLR3 signaling is its association with tumor cell growth
[33,34]
. TLR3 has
also been identified as an endogenous sensor of necrosis that amplifies
inflammation in settings that are not associated with viral dsRNA, such as
septic peritonitis and also in ischemic gut injury
[33,34]
. These data suggest
that, in addition to recognition of viral dsRNA, TLR3 might also play a key
role as a sensor of endogenously derived nonviral signals that play a role in
autoimmunity and immune surveillance.
428
The identification of patients with mutations in key TLR3 signaling compo-
nents has served as an experiment of nature that played a key role in eluci-
dating the biological function of TLR3 in humans. Patients with mutations
in genes encoding TLR3 have a selective immunodeficiency manifested by
recurrent episodes of HSV-1 encephalitis
[27,28]
. Interestingly, TLR3 defi-
ciency is specifically associated with only HSV encephalitis in children, as
these individuals are reported to have normal resistance to other pathogens
[17,28,29]
. These observations indicate a nonredundant role for TLR3 in
sensing HSV-1 in humans. In fact, to date, TLR3 is the only TLR shown to
play a nonredundant role in host defense against at least one microbe.
TLR7
TLR7 is an endosomal sensor that recognizes ssRNA viruses and synthetic
oligoribonucleotides (ORN) such as imidazoquinoline, imiquimod, and
R-848
[2,14,18]
. The ORNs sensed by TLR7 are typically AU rich. TLR7 is
primarily, but not only, expressed in hematopoietic cells such as plasma-
cytoid DCs (pDCs) and B cells
[35]
. Upon engagement with nucleic acid
ligands, TLR7 translocates from the endoplasmic reticulum (ER) to a spe-
cialized lysosome-related organelle, a process that requires adaptor protein
3 and Slc15a4
[36,37]
. TLR7 signals through the cytosolic adaptor MyD88
and induces both type I IFN and an inflammatory response. MyD88 asso-
ciates with IRAK1/4, TRAF3, and IKKα, leading to the phosphorylation,
activation, and translocation of IRF7, and induces transcription of IFN-α/β
genes
[14,18]
. To induce inflammatory cytokines, MyD88 associates with
IRAK1/4, triggers TRAF6, and activates NF-κB to induce inflammatory cyto-
kines
[13,16]
. While pDCs detect RNA viruses through TLR7, they detect
DNA viruses through TLR9
[35]
. In fact the expression pattern of TLR7
often correlates with TLR9 expression and both have been implicated in the
development of autoimmunity
[35]
. TLR7 has been directly linked to the
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