Proximal effects of Toll-like receptor activation in dendritic cells
-
Upload
colin-watts -
Category
Documents
-
view
214 -
download
0
Transcript of Proximal effects of Toll-like receptor activation in dendritic cells
![Page 1: Proximal effects of Toll-like receptor activation in dendritic cells](https://reader035.fdocuments.us/reader035/viewer/2022081205/57501f091a28ab877e93aeaf/html5/thumbnails/1.jpg)
Proximal effects of Toll-like receptor activation indendritic cellsColin Watts1, Rossana Zaru1, Alan R Prescott1,Robert P Wallin1,2 and Michele A West1
Toll-like receptor (TLR) signals induce dendritic cell (DC)
differentiation and influence the immunological outcome of
their interactions with T cells. Recent in vitro studies
demonstrate that TLR signals also trigger striking
reorganisation of the DC vacuolar compartments, the
cytoskeleton and the machinery of protein translation and
turnover. Moreover, TLR ligation within endosomes and
phagosomes appears to establish organelle autonomous
signals. These changes, which mostly occur within minutes to a
few hours after TLR engagement, are adaptations relevant to
the antigen capture, processing and migratory phases of the
DC life history.
Addresses1 Division of Cell Biology and Immunology, College of Life Sciences,
University of Dundee, Dundee DD1 5EH, United Kingdom2 Center for Infectious Medicine, F59, Department of Medicine,
Karolinska Institutet, Karolinska University Hospital, S-141 86
Stockholm, Sweden
Corresponding author: Watts, Colin ([email protected])
Current Opinion in Immunology 2007, 19:73–78
This review comes from a themed issue on
Antigen processing and recognition
Edited by Jose Villadangos and Peter van Endert
Available online 4th December 2006
0952-7915/$ – see front matter
# 2006 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2006.11.014
IntroductionIt is now almost ten years since the appearance of the first
detailed studies on the effects of lipopolysaccharide
(LPS) on antigen capture, MHC biosynthesis and antigen
presentation by cultured dendritic cells (DCs) [1,2].
Although the details of how cultured human and murine
DCs responded differed [3], those studies set the scene
for a still developing story of cell biological adaptations
triggered by microbial products and inflammatory med-
iators that boost the performance of DCs as antigen
presenting cells (reviewed in [4–6]). It is now clear that
Toll-like receptor (TLR) ligands not only stimulate tran-
scription of cytokines and co-stimulatory molecules but
also signal an array of responses that affect the membrane
vacuolar system, the cytoskeleton and the machinery of
protein translation and degradation. The purpose of this
review is to highlight recent developments in this area,
www.sciencedirect.com
i.e. the cell biological changes that occur in DCs proximal
to (i.e. soon after) Toll-like receptor (TLR) activation.
TLR signalling per se has been reviewed elsewhere [7,8]
and is not covered here.
TLR signalling effects on endocytosisand the cytoskeletonOne of the earliest responses to TLR ligands that can be
observed in DCs expanded from murine bone marrow
and spleen is a transient increase in endocytic activity
[9,10] caused by enhanced membrane ruffling and macro-
pinocytosis [10]. Phagocytosis is similarly stimulated by
TLR engagement, as is phagosome maturation (see
below) [11]. Simultaneous exposure to antigen and
LPS enhanced antigen presentation on both class I and
class II MHC molecules compared with sequential expo-
sure to antigen and then to LPS [10]. The TLR-driven
actin-dependent endocytic response was blocked by a
combination of Erk and p38 inhibitors and was coincident
with a striking disassembly, again transient, of actin-rich
podosomes, which are thought to be involved in cell
invasiveness [10–12]. These studies indicate that antigen
capture and migration might be mutually exclusive and,
via TLR signals, switchable modes of operation for the
DC. Indeed, in vitro, DCs experience a transient loss of
migratory capacity during the phase of enhanced macro-
pinocytosis and podosome disappearance (MAW et al.,unpublished). LPS triggered an irreversible loss of podo-
somes in human monocyte-derived DCs but on a longer
timescale compared with murine DCs [13,14]. In human
DCs, LPS-induced prostaglandin E2 (PGE2) production
appeared to be crucial because podosome loss was
blocked by indomethacin and triggered by addition of
PGE2 [14]. Further studies are needed to clarify the role
of podosomes in DC biology.
The actin cytoskeleton has to perform different functions
at different points in the life history of a DC. The core
machinery of actin polymerisation, for example the Rho
family GTPases Rac1 and Rac2, are involved in DC
endocytosis, migration in vivo and exploratory interactions
with T cells [15–19]. TLR signalling seems to regulate the
actin cytoskeleton acutely, for example through phosphor-
ylation of specific components and by inducing expression
of other actin network regulators. These include the
scavenger receptor MARCO [20] and the actin cross-
linking protein fascin [21,22], which are expressed only
in mature DCs and are in part responsible for their dis-
tinctive morphology and ability to interact with T cells.
Current Opinion in Immunology 2007, 19:73–78
![Page 2: Proximal effects of Toll-like receptor activation in dendritic cells](https://reader035.fdocuments.us/reader035/viewer/2022081205/57501f091a28ab877e93aeaf/html5/thumbnails/2.jpg)
74 Antigen processing and recognition
Circumscribed TLR signals in the endocyticpathwayThe lumenal side of endosomes and phagosomes is
topologically equivalent to the cell surface yet increasing
evidence indicates that TLR signalling from these two
locations is not equivalent. For example, TLR4 propa-
gates one response when signalling from the cell surface,
but provides a more circumscribed signal when engaged
within endosomes or phagosomes. This can lead to ‘orga-
nelle autonomous’ effects (i.e. responses that are confined
to the signalling organelle). For example, in macrophages,
phagosome maturation and fusion with lysosomes was
accelerated in phagosomes that harbour TLR-signalling
entities (e.g. bacteria) compared with phagosomes that
contain non-signalling loads, for example apoptotic cells
[11]. A second group that used IgG- or mannose-opso-
nised beads with or without TLR4 or TLR2 ligands did
not observe TLR-enhanced fusion with lysosomes or
TLR-increased acidification in macrophages [23�]. The
reasons for these different results are not clear, but it is
possible that signalling following opsonin engagement of
Fc or mannose receptors masks differences resulting from
TLR ligation. In immature DCs, unlike macrophages,
phagosomes maintain a neutral, even slightly alkaline, pH
owing to recruitment of the superoxide-generating
NADPH oxidase NOX2 complex [24��]. These studies,
which demonstrated enhanced antigen cross-presentation
from NOX2-controlled phagosomes, were performed in
TLR ligand free phagosomes. It will be interesting to
make similar pH measurements under conditions in
which intra-phagosomal TLR-signalling is also occurring
to see how NOX2-regulated phagosomal pH and cross-
presentation are affected.
In this context, a recent study has explored the functional
consequences of ‘phagosome autonomous’ signalling in
DCs and has demonstrated enhanced peptide–MHC
class II generation (and antigen presentation) within
TLR-signalling phagosomes [25��]. Differential genera-
tion of peptide–MHC complexes occurred even when
TLR-signalling and non-signalling phagosomes were in
the same cell. Externally applied LPS had a much less
potent effect than LPS confined to the antigen-loaded
bead. The underlying mechanisms that modulate phago-
some maturation and antigen presentation in TLR-sig-
nalling phagosomes have not been fully resolved to date.
The authors found a partial failure to process the invariant
chain chaperone in non-signalling phagosomes compared
with LPS-signalling phagosomes [25��]. Although pro-
tease levels appeared to be equivalent, it might be
worthwhile assessing their activity in situ in both signal-
ling and non-signalling phagosomes, for example using
bead-tethered radiochemical probes that react with pro-
tease active sites, as reported previously [26]. As dis-
cussed by Blander and Medzhitov [27], their study
demonstrates the potential for biasing antigen presenta-
tion towards ‘foreign’ at the expense of ‘self’ when those
Current Opinion in Immunology 2007, 19:73–78
entities are separately packaged in different phagosomes.
Such discrimination cannot operate in other scenarios, for
example in situations in which infected (i.e. TLR-stimu-
lating) apoptotic cells are phagocytosed. In other situa-
tions, MHC class II peptide presentation obviously occurs
without a TLR stimulus (e.g. in tolerogenic DCs) [28].
Can the concept of selective presentation of antigens
captured concomitant with TLR signalling be extended
to authentic physiological situations? A recent study on
the Toxoplasma gondii parasite suggests that it can. T.gondii profilin, a ligand for TLR11 [29�], is immunodo-
minant in the CD4 T-cell response. Yarovinsky et al.[30��] showed that this immunodominance depended
on expression of TLR11, MyD88 and MHC class II on
the same CD8+ DC. The TLR11–MyD88 signalling unit
enhanced profilin binding and uptake as well as DC
maturation. This study extends earlier evidence that
chemical coupling of antigens to TLR ligands boosts
immunogenicity [31,32] and, as noted by Yarovinsky
et al. [30��], raises the possibility that other immunodo-
minant pathogen-encoded proteins or protein-linked
entities might also be TLR stimulators.
Evidence is emerging that distinct TLR signals might
emanate from sub-domains of the endocytic pathway, at
least in plasmacytoid DCs (pDCs). To date, this is only well
documented for TLR9 — a member of the subset of TLRs
that recognize nucleic acids (TLRs 3, 7 8 and 9) within
endosomes. Upon recognition of different types of CpG-
containing DNA sequences, TLR9 in pDCs either triggers
production of type I interferon (CpG-A) or drives pDC
maturation (CpG-B), as measured by elevated expression
of costimulatory molecules [33]. In pDCs, multimeric A-
type CpG and monomeric B-type CpG accumulate in early
and late endosomes, respectively, for reasons that are
unresolved[34��,35�Nonetheless, this compartmental spe-
cificity seems to control the immunological outcome, partly
at least because a complex of the transcription factor IRF7
and the signallingadaptorMyD88,both ofwhichare known
to be needed for Type I interferon production, is recruited
to early endosomes in pDC [34��].
TLR9 can be redirected to the cell surface by substitution
of its trans-membrane and cytosolic domain with that
from TLR4, and can signal from this location in response
to mammalian DNA (but not virally encapsulated DNA)
[36�]. Thus, it is the intracellular sequestration of TLR9
that normally prevents a response to ‘self’ DNA. Inter-
estingly, the redirected TLR9/TLR4 chimera works in
conventional DCs but not in pDCs, underscoring the
distinct features of TLR9 function in pDCs [36�].
TLR signalling effects on MHC class II andmembrane trafficDC maturation, driven typically by LPS signalling, results
in dramatically increased levels of cell surface MHC class
www.sciencedirect.com
![Page 3: Proximal effects of Toll-like receptor activation in dendritic cells](https://reader035.fdocuments.us/reader035/viewer/2022081205/57501f091a28ab877e93aeaf/html5/thumbnails/3.jpg)
Proximal effects of Toll-like receptor activation in dendritic cells Watts et al. 75
I and class II molecules in human and murine DCs [1,2].
LPS induces the rapid elaboration of MHC class II
containing membrane tubules from late endosome and
lysosome compartments driven by structural rearrange-
ments of multivesicular late endosomes and lysosomes
[37–39]. These rearrangements serve to redistribute anti-
gen-loaded MHC class II molecules to the cell surface
and, in the presence of cognate T cells, to the antigen-
presenting cell–T cell interface [40]. Most data now
indicate that peptide–MHC class II complexes are con-
tinuously generated in immature DCs but are degraded
before or after transient exposure on the cell surface
(reviewed in [6]). LPS signals a shut-down of peptide–
MHC class II endocytosis, thus extending their half-life
and ‘fixing’ recently assembled peptide–MHC com-
plexes on the cell surface [1,41]. TLR signalling also
boosts endosomal–lysosomal acidification [42], which,
through various mechanisms, might further boost the
quality, quantity and detectability of peptide–MHC com-
plex formation [5,6,43] in maturing DCs.
An incompletely resolved issue is how DC maturation
stabilizes MHC class II molecules on the cell surface.
Although actin-dependent macropinocytosis eventually
ceases as DCs mature, immature and mature DCs have
roughly equivalent numbers of clathrin-coated pits
through which MHC molecules can still be internalised
[16,17]. A clue as to how MHC class II traffic might be
regulated in DCs came from a demonstration that trans-
genic or in vitro overexpression of the E3-ligase cMIR
leads to down-regulation of MHC class II molecules
through ubiquitination of lysine 225 in the b chain
[44�]. Two new studies show that this residue is oligo-
ubiquitinated in immature DCs but not in mature DCs
[45�,46� Mutation of lysine 225 blocked ubiquitination
and resulted in elevated class II MHC expression on the
cell surface, even in immature DCs. Conversely, fusion of
ubiquitin to the MHC class II b chain prevented its
surface display, even in mature DCs [45�]. It will be
interesting to establish whether TLR-regulated MHC
class II b chain ubiquitination is caused by reduced
activity of a specific E3 ligase (perhaps cMIR), by
increased activity of a de-ubiquitinating enzyme, or both.
Protein translation and turnoverIn addition to the vacuolar and cytoskeleton systems
discussed above, TLR signalling induces striking changes
in protein synthesis and turnover caused, in part, by the
well-documented changes in gene expression that occur
[47–49], including increased synthesis of MHC molecules
and antigen-processing machinery [1,37,50,51]. Other
studies report more enigmatic cellular changes. For exam-
ple, within four hours of LPS challenge, DCs begin to
accumulate ubiquitinated proteins at distinct foci termed
DC aggresome-like induced structures (DALIS). These
structures are specific to DCs and are only seen when
protein synthesis is ongoing [52]. Prematurely terminated
www.sciencedirect.com
translation products become ubiquitinated in DALIS and
seem to stimulate their formation [53]. These and other
types of defective ribosomal products (DRIPs) are known
to provide a preferred substrate for peptide generation in
the MHC class I antigen processing pathway [54]. How-
ever, DRIP targeting to DALIS might actually disfavour,
at least in the short term, their ultimate presentation on
MHC class I molecules because they become markedly
resistant to proteasomal degradation with a half-life
extended by some 20-fold. Therefore, sequestration of
endogenously generated DRIPs in maturing DCs might
favour exogenous antigen substrates channelled into the
class I MHC cross-presentation pathway and that were
not incorporated into DALIS. DALIS remain enigmatic
structures but their properties and rapid appearance sug-
gests that protein translation and turnover are subject to
acute control by TLR signals.
ConclusionsThe focus of many studies on DC responses to microbial
and inflammatory signals has rightly been on how they
modulate the ability of DCs to engage and then stimulate
or tolerise T cells. At least for a tissue-resident DC, the
encounter with T cells might take place a long time after
and a long distance away from its initial exposure to
antigen and TLR stimuli. A lot has to happen before
DCs reach lymphoid organs, therefore the same stimuli
that prepare DCs for interactions with T cells might also
be expected to affect key earlier events including antigen
capture, antigen processing and migration. Evidence
reviewed here suggests that this is indeed the case.
The challenge for the future is to confirm, refine or
rewrite the story based on observations of DCs in situas they respond to stimuli channelled through TLRs or
through other sensors. At least in vitro, DC-sensing of a
bacterially derived stimulus could rapidly transmit the
resulting Ca2+ signal to cells located more than 100 mm
away through fine (50–200 nm) tubular connections
between cells [55�]. Whether similar connectivity exists
in vivo is not yet known but it might permit an amplified
and integrated response not dependent on diffusion of
soluble mediators. Imaging some of the sub-cellular
events discussed in this review in vivo poses some major
technical challenges, but it is clear that DCs can respond
as rapidly to TLR stimuli in vivo as they do in vitro. For
example, egress of rat intestinal DCs into afferent lym-
phatics could be detected within two hours of orally
feeding the TLR7 and TLR8 agonist R848 and was
maximal between four and eight hours [56].
LPS activates the classical MAP kinase (Erk1/2), the so-
called stress-activated (p38 and Jnk) protein kinase cas-
cades, and other signalling pathways within 5–15 min of
LPS detection, as documented in many studies [7], so it is
not surprising that changes much faster than those nor-
mally associated with DC maturation can occur. Blockade
Current Opinion in Immunology 2007, 19:73–78
![Page 4: Proximal effects of Toll-like receptor activation in dendritic cells](https://reader035.fdocuments.us/reader035/viewer/2022081205/57501f091a28ab877e93aeaf/html5/thumbnails/4.jpg)
76 Antigen processing and recognition
of the MAP kinases, particularly p38 and Erk, inhibits
not only cytokine production but also more proximal
LPS-triggered events such as actin rearrangements [10]
and phagosome maturation [11]. Because there are at
least ten different MAP kinase activated kinases
(including isoforms) immediately downstream of the
MAP kinases, each of which has multiple substrates,
the potential for modulating cell behaviour is consider-
able [57]. Future studies are likely to explore how these
and other signalling pathways modulate the cellular
systems discussed here and how different TLR
signals can be propagated from subcellular membrane
compartments.
AcknowledgementsWork in the authors’ laboratory is supported by the Medical ResearchCouncil and the Wellcome Trust.
References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:
� of special interest�� of outstanding interest
1. Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A:Inflammatory stimuli induce accumulation of MHC class IIcomplexes on dendritic cells. Nature 1997, 388:782-787.
2. Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, Mirza A, Inaba K,Steinman RM, Mellman I: Developmental regulation of MHCclass II transport in mouse dendritic cells. Nature 1997,388:787-792.
3. Watts C: Immunology. Inside the gearbox of the dendritic cell.Nature 1997, 388:724-725.
4. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S:Antigen presentation and T cell stimulation by dendritic cells.Annu Rev Immunol 2002, 20:621-667.
5. Trombetta ES, Mellman I: Cell biology of antigen processingin vitro and in vivo. Annu Rev Immunol 2005, 23:975-1028.
6. Villadangos JA, Schnorrer P, Wilson NS: Control of MHC class IIantigen presentation in dendritic cells: a balance betweencreative and destructive forces. Immunol Rev 2005,207:191-205.
7. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol2004, 4:499-511.
8. O’Neill LA: How Toll-like receptors signal: what we know andwhat we don’t know. Curr Opin Immunol 2006, 18:3-9.
9. Granucci F, Ferrero E, Foti M, Aggujaro D, Vettoretto K,Ricciardi-Castagnoli P: Early events in dendritic cell maturationinduced by LPS. Microbes Infect 1999, 1:1079-1084.
10. West MA, Wallin RP, Matthews SP, Svensson HG, Zaru R,Ljunggren HG, Prescott AR, Watts C: Enhanced dendritic cellantigen capture via Toll-like receptor-induced actinremodeling. Science 2004, 305:1153-1157.
11. Blander JM, Medzhitov R: Regulation of phagosome maturationby signals from Toll-like receptors. Science 2004,304:1014-1018.
12. Linder S, Kopp P: Podosomes at a glance. J Cell Sci 2005,118:2079-2082.
13. Burns S, Hardy SJ, Buddle J, Yong KL, Jones GE, Thrasher AJ:Maturation of DC is associated with changes in motilecharacteristics and adherence. Cell Motil Cytoskeleton 2004,57:118-132.
14. van Helden SF, Krooshoop DJ, Broers KC, Raymakers RA,Figdor CG, van Leeuwen FN: A critical role for prostaglandin E2
Current Opinion in Immunology 2007, 19:73–78
in podosome dissolution and induction of high-speedmigration during dendritic cell maturation. J Immunol 2006,177:1567-1574.
15. Lindquist RL, Shakhar G, Dudziak D, Wardemann H, Eisenreich T,Dustin ML, Nussenzweig MC: Visualizing dendritic cell networksin vivo. Nat Immunol 2004, 5:1243-1250.
16. West MA, Prescott AR, Eskelinen EL, Ridley AJ, Watts C:Rac is required for constitutive macropinocytosis by dendriticcells but does not control its downregulation. Curr Biol 2000,10:839-848.
17. Garrett WS, Chen LM, Kroschewski R, Ebersold M, Turley S,Trombetta S, Galan JE, Mellman I: Developmental controlof endocytosis in dendritic cells by Cdc42. Cell 2000,102:325-334.
18. Kerksiek KM, Niedergang F, Chavrier P, Busch DH, Brocker T:Selective Rac1 inhibition in dendritic cells diminishesapoptotic cell uptake and cross-presentation in vivo.Blood 2005, 105:742-749.
19. Benvenuti F, Hugues S, Walmsley M, Ruf S, Fetler L, Popoff M,Tybulewicz VL, Amigorena S: Requirement of Rac1 and Rac2expression by mature dendritic cells for T cell priming.Science 2004, 305:1150-1153.
20. Granucci F, Petralia F, Urbano M, Citterio S, Di Tota F,Santambrogio L, Ricciardi-Castagnoli P: The scavenger receptorMARCO mediates cytoskeleton rearrangements in dendriticcells and microglia. Blood 2003, 102:2940-2947.
21. Ross R, Jonuleit H, Bros M, Ross XL, Yamashiro S, Matsumura F,Enk AH, Knop J, Reske-Kunz AB: Expression of the actin-bundling protein fascin in cultured human dendritic cellscorrelates with dendritic morphology and cell differentiation.J Invest Dermatol 2000, 115:658-663.
22. Al-Alwan MM, Rowden G, Lee TD, West KA: Fascin is involved inthe antigen presentation activity of mature dendritic cells.J Immunol 2001, 166:338-345.
23.�
Yates RM, Russell DG: Phagosome maturation proceedsindependently of stimulation of Toll-like receptors 2 and 4.Immunity 2005, 23:409-417.
In apparent contrast to [11], this study did not detect any difference inphagosome maturation or acidification when IgG or mannose-opsonisedparticles were coated with TLR2 or TLR4 ligands. As discussed in [27], it ispossible that opsonisation might itself maximally trigger phagosomematuration, thus masking effects caused by TLR ligation.
24.��
Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P,Moura IC, Lennon-Dumenil AM, Seabra MC, Raposo G,Amigorena S: NOX2 controls phagosomal pH to regulateantigen processing during crosspresentation by dendriticcells. Cell 2006, 126:205-218.
Through the alkalinising activity of NOX2, DC phagosomes are main-tained at a pH close to neutral in contrast to macrophages, in whichphagosomes progressively acidify. Antigen cross-presentation isimproved in DCs by a reduction in destructive processing. Given theevidence that lysosomal acidification is enhanced as DCs mature [42], itwill be interesting to see whether TLR ligation within DC phagosomesaffects this pH control.
25.��
Blander JM, Medzhitov R: Toll-dependent selection ofmicrobial antigens for presentation by dendritic cells.Nature 2006, 440:808-812.
This is a conceptually important study that investigates the conse-quences of phagosome autonomous TLR signalling in DCs, and showsselective presentation of antigens from phagosomes in which TLRs wereactivated. The authors argue (see also [27]) that this might bias antigenpresentation towards ‘foreign’ and away from ‘self’ when individual DCshave ingested both types of entity.
26. Lennon-Dumenil AM, Bakker AH, Maehr R, Fiebiger E,Overkleeft HS, Rosemblatt M, Ploegh HL, Lagaudriere-Gesbert C:Analysis of protease activity in live antigen-presentingcells shows regulation of the phagosomal proteolyticcontents during dendritic cell activation. J Exp Med 2002,196:529-540.
27. Blander JM, Medzhitov R: On regulation of phagosomematuration and antigen presentation. Nat Immunol 2006,7:1029-1035.
www.sciencedirect.com
![Page 5: Proximal effects of Toll-like receptor activation in dendritic cells](https://reader035.fdocuments.us/reader035/viewer/2022081205/57501f091a28ab877e93aeaf/html5/thumbnails/5.jpg)
Proximal effects of Toll-like receptor activation in dendritic cells Watts et al. 77
28. Steinman RM, Hawiger D, Nussenzweig MC: Tolerogenicdendritic cells. Annu Rev Immunol 2003, 21:685-711.
29.�
Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN,Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S et al.:TLR11 activation of dendritic cells by a protozoan profilin-likeprotein. Science 2005, 308:1626-1629.
Together with [30��], this study shows that that T. gondii profilin is a TLR11ligand and that this property is responsible for its immunodominance. Thestudy provides in vivo evidence that ligation of TLRs at the time of antigencapture enhances antigen capture and presentation.
30.��
Yarovinsky F, Kanzler H, Hieny S, Coffman RL, Sher A:Toll-like receptor recognition regulates immunodominancein an antimicrobial CD4+ T cell response. Immunity 2006,25:655-664.
See annotation to [29�].
31. Maurer T, Heit A, Hochrein H, Ampenberger F, O’Keeffe M,Bauer S, Lipford GB, Vabulas RM, Wagner H: CpG-DNA aidedcross-presentation of soluble antigens by dendritic cells.Eur J Immunol 2002, 32:2356-2364.
32. Wille-Reece U, Flynn BJ, Lore K, Koup RA, Kedl RM, Mattapallil JJ,Weiss WR, Roederer M, Seder RA: HIV Gag protein conjugatedto a Toll-like receptor 7/8 agonist improves the magnitude andquality of Th1 and CD8+ T cell responses in nonhumanprimates. Proc Natl Acad Sci USA 2005, 102:15190-15194.
33. Krieg AM: CpG motifs in bacterial DNA and their immuneeffects. Annu Rev Immunol 2002, 20:709-760.
34.��
Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A,Taya C, Taniguchi T: Spatiotemporal regulation of MyD88–IRF-7signalling for robust type-I interferon induction. Nature 2005,434:1035-1040.
This study shows that, in pDCs, the MyD88–IRF7 signalling modulerequired for TLR9-driven type I interferon production targets to earlyendosomes, which also accumulate the inducing CpG-A type DNA. Bymanipulating CpG DNA trafficking using a cationic lipid the authors couldinduce interferon production in otherwise refractory conventional DCs.See also [35�].
35.�
Guiducci C, Ott G, Chan JH, Damon E, Calacsan C, Matray T,Lee KD, Coffman RL, Barrat FJ: Properties regulating the natureof the plasmacytoid dendritic cell response to Toll-likereceptor 9 activation. J Exp Med 2006, 203:1999-2008.
Complementary to [34��], this study illustrates how sub-domains of theendocytic pathway in pDCs accumulate different types of CpG-contain-ing DNA that drive either type I interferon production (CpG-A) or pDCmaturation (CpG-B).
36.�
Barton GM, Kagan JC, Medzhitov R: Intracellular localization ofToll-like receptor 9 prevents recognition of self DNA butfacilitates access to viral DNA. Nat Immunol 2006, 7:49-56.
By switching the transmembrane and cytosolic domains of TLR9 for thoseof TLR4, the authors show that the hybrid cell surface-localized TLR9,unlike wild-type TLR9, now recognizes mammalian DNA but not encap-sulated viral DNA. Recognition of self DNA is normally avoided because itis degraded before accessing sequestered wild-type TLR9.
37. MacAry PA, Lindsay M, Scott MA, Craig JI, Luzio JP, Lehner PJ:Mobilization of MHC class I molecules from late endosomesto the cell surface following activation of CD34-derivedhuman Langerhans cells. Proc Natl Acad Sci USA 2001,98:3982-3987.
38. Kleijmeer M, Ramm G, Schuurhuis D, Griffith J, Rescigno M,Ricciardi-Castagnoli P, Rudensky AY, Ossendorp F, Melief CJ,Stoorvogel W et al.: Reorganization of multivesicular bodiesregulates MHC class II antigen presentation by dendritic cells.J Cell Biol 2001, 155:53-63.
39. Chow A, Toomre D, Garrett W, Mellman I: Dendritic cellmaturation triggers retrograde MHC class II transportfrom lysosomes to the plasma membrane. Nature 2002,418:988-994.
40. Boes M, Bertho N, Cerny J, Op den Brouw M, Kirchhausen T,Ploegh H: T cells induce extended class II MHC compartmentsin dendritic cells in a Toll-like receptor-dependent manner.J Immunol 2003, 171:4081-4088.
41. Wilson NS, El-Sukkari D, Villadangos JA: Dendritic cellsconstitutively present self antigens in their immature state in
www.sciencedirect.com
vivo and regulate antigen presentation by controlling the ratesof MHC class II synthesis and endocytosis. Blood 2004,103:2187-2195.
42. Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I:Activation of lysosomal function during dendritic cellmaturation. Science 2003, 299:1400-1403.
43. Inaba K, Turley S, Iyoda T, Yamaide F, Shimoyama S, Reis eSousa C, Germain RN, Mellman I, Steinman RM: The formation ofimmunogenic major histocompatibility complex class II–peptide ligands in lysosomal compartments of dendriticcells is regulated by inflammatory stimuli. J Exp Med 2000,191:927-936.
44.�
Ohmura-Hoshino M, Matsuki Y, Aoki M, Goto E, Mito M,Uematsu M, Kakiuchi T, Hotta H, Ishido S: Inhibition of MHCclass II expression and immune responses by c-MIR.J Immunol 2006, 177:341-354.
This is an important study that, together with earlier data, shows that theE3 ubiquitin ligase c-MIR functions as an immune modulator targetingboth B7-2 and MHC class II molecules. The authors further show that aconserved lysine (225) in the b-chain of MHC class II is ubiquitinated by c-MIR.
45.�
Shin J-S, Ebersold M, Pypaert M, Delamarre L, Hartley A,Mellman I: Surface expression of MHC class II in dendriticcells is controlled by regulated ubiquitination. Nature 2006,444:115-118.
In this article, the authors demonstrate that ubiquitination of lysine 225 inthe b-chain of MHC class II (see [44�]) occurs in immature DCs but not inLPS-matured DCs, and that it is responsible for intracellular retention ofpeptide-loaded MHC in immature DCs. Thus, TLR signalling controls thebalance of ubiquitination and de-ubiquitination of MHC class II andperhaps other proteins. See also [46�].
46.�
van Niel G, Wubbolts R, Broeke T, Buschow S, Ossendorp F,Melief C, Raposo G, Balkom B, Stoorvogel W: Dendritic cellsregulate MHC class II exposure by oligo-ubiquitination.Immunity 2006, in press.
This article contains data similar to that in [45�].
47. Hashimoto SI, Suzuki T, Nagai S, Yamashita T, Toyoda N,Matsushima K: Identification of genes specifically expressed inhuman activated and mature dendritic cells through serialanalysis of gene expression. Blood 2000, 96:2206-2214.
48. Huang Q, Liu D, Majewski P, Schulte LC, Korn JM, Young RA,Lander ES, Hacohen N: The plasticity of dendritic cellresponses to pathogens and their components. Science 2001,294:870-875.
49. Granucci F, Vizzardelli C, Virzi E, Rescigno M, Ricciardi-Castagnoli P: Transcriptional reprogramming of dendritic cellsby differentiation stimuli. Eur J Immunol 2001, 31:2539-2546.
50. Rescigno M, Citterio S, Thery C, Rittig M, Medaglini D,Pozzi G, Amigorena S, Ricciardi Castagnoli P: Bacteria-inducedneo-biosynthesis, stabilization, and surface expressionof functional class I molecules in mouse dendritic cells.Proc Natl Acad Sci USA 1998, 95:5229-5234.
51. Gil-Torregrosa BC, Lennon-Dumenil AM, Kessler B,Guermonprez P, Ploegh HL, Fruci D, van Endert P, Amigorena S:Control of cross-presentation during dendritic cellmaturation. Eur J Immunol 2004, 34:398-407.
52. Lelouard H, Gatti E, Cappello F, Gresser O, Camosseto V, Pierre P:Transient aggregation of ubiquitinated proteins duringdendritic cell maturation. Nature 2002, 417:177-182.
53. Lelouard H, Ferrand V, Marguet D, Bania J, Camosseto V, David A,Gatti E, Pierre P: Dendritic cell aggresome-like inducedstructures are dedicated areas for ubiquitination and storageof newly synthesized defective proteins. J Cell Biol 2004,164:667-675.
54. Yewdell JW, Nicchitta CV: The DRiP hypothesis decennial:support, controversy, refinement and extension. TrendsImmunol 2006, 27:368-373.
55.�
Watkins SC, Salter RD: Functional connectivity betweenimmune cells mediated by tunneling nanotubules.Immunity 2005, 23:309-318.
This study shows that dendritic cells can communicate with each otherand with other cells through ‘tunnelling nanotubes’. A single cell sensing a
Current Opinion in Immunology 2007, 19:73–78
![Page 6: Proximal effects of Toll-like receptor activation in dendritic cells](https://reader035.fdocuments.us/reader035/viewer/2022081205/57501f091a28ab877e93aeaf/html5/thumbnails/6.jpg)
78 Antigen processing and recognition
stimulus was able to communicate this through a network of cells up to100 mM away through connecting 50–200 nm diameter membranetubules.
56. Yrlid U, Milling SW, Miller JL, Cartland S, Jenkins CD,MacPherson GG: Regulation of intestinal dendritic cellmigration and activation by plasmacytoid dendritic cells,
Current Opinion in Immunology 2007, 19:73–78
TNF-a and type 1 IFNs after feeding a TLR7/8 ligand. J Immunol2006, 176:5205-5212.
57. Roux PP, Blenis J: ERK and p38 MAPK-activated proteinkinases: a family of protein kinases with diverse biologicalfunctions. Microbiol Mol Biol Rev 2004, 68:320-344.
www.sciencedirect.com