Activation of dendritic cells: translating innate into adaptive immunity

Activation of dendritic cells: translating innate into
adaptive immunity
Caetano Reis e Sousa
Innate recognition of infection in vertebrates can lead to the
induction of adaptive immune responses through activation of
dendritic cells (DCs). DCs are activated directly by conserved
pathogen molecules and indirectly by inflammatory mediators
produced by other cell types that recognise such molecules. In
addition, it is likely that DCs are activated by poorly characterised
cellular stress molecules and by disturbances in the internal
milieu. The multiplicity of innate pathways for DC activation may
have evolved to ensure that any signs of infection are detected
early, before overwhelming pathogen replication. Understanding
which of these signs are both necessary and sufficient to convert
DCs into the immunostimulatory antigen-presenting cells that
prime appropriate effector T cells may hold the key to improved
strategies for vaccination and immunotherapy.
Addresses
Immunobiology Laboratory, Cancer Research UK, London Research
Institute, Lincoln’s Inn Fields Laboratories, 44 Lincoln’s Inn Fields,
London WC2A 3PX, UK
e-mail: [email protected]
it is not surprising that adaptive immunity takes its cues
from the innate immune system. Indeed, as postulated
by Janeway [1], it is now abundantly clear that innate
signalling precedes, and is essential for, the generation of
T-cell and B-cell responses. Central to this process are
the dendritic cells (DCs), a heterogeneous family of
leukocytes that integrate innate information and convey
it to lymphocytes. Innate stimulation of DCs can trigger
their differentiation into immunogenic antigen-presenting cells (APCs) capable of priming and sustaining the
expansion of naı̈ve T cells. In addition, DCs direct T-cell
effector differentiation, thus being responsible for ensuring that the specificity of the innate immune system,
which distinguishes between many classes of potential
pathogens, is translated into an equally specific class of
adaptive immune response. This review focuses on our
emerging understanding of the mechanisms involved in
innate activation of DCs and how they may impact on
immunity.
Innate activation of dendritic cells
Current Opinion in Immunology 2004, 16:21–25
This review comes from a themed issue on
Innate immunity
Edited by Bruce Beutler and Jules Hoffmann
0952-7915/$ – see front matter
ß 2003 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2003.11.007
Abbreviations
APC
antigen-presenting cell
CpG ODN CpG-containing oligonucleotide
DC
dendritic cell
dsRNA
double-stranded RNA
IFN
interferon
IFN-I
receptor for type I interferons
IL
interleukin
LPS
lipopolysaccharide
Mo-DC
monocyte-derived DC
NK
natural killer
PAMP
pathogen-associated molecular pattern
PDC
plasmacytoid DC
PKR
protein kinase R
PRR
pattern-recognition receptor
Th
T helper
TLR
Toll-like receptor
TNF
tumour necrosis factor
Introduction
The adaptive immune system, found exclusively in vertebrates, evolved from an ancient innate defence
mechanism common to all metazoans. Given this past,
www.sciencedirect.com
There are several distinct mechanisms leading to innate
DC activation, all of which probably share an evolutionary
link to infection [2]. In this review, a distinction is
made between pattern recognition pathways, which allow
direct or indirect detection of conserved molecular signatures of potential pathogens (the so-called ‘pathogenassociated molecular patterns’, or PAMPs; [1]), and
PAMP-independent DC activation in response to selfmolecules or alterations in the internal milieu (Figure 1).
Although interactions with CD4þ and CD8þ T cells can
also induce DC activation [3–6], such ‘adaptive’ signals
will not be discussed.
PAMP-dependent dendritic cell activation
Cells of the innate immune system, including DCs,
possess pattern-recognition receptors (PRRs) that recognise PAMPs from viruses, bacteria, fungi and protozoa.
The best-studied PRRs are the Toll-like receptors
(TLRs), discovered a mere six years ago [7]. The role
of TLRs in DC biology has been reviewed recently [8]
and only the most salient points will be reiterated here.
A major dichotomy in TLR expression has been observed
in human blood DC subtypes. Thus, human plasmacytoid
DCs (PDCs) fail to express TLR4 and do not respond to
lipopolysaccharide (LPS), whereas CD11cþ DCs and
monocyte-derived DCs (Mo-DCs) are very sensitive to
LPS stimulation even if they only express low levels of
TLR4 [9–13]. In contrast, human blood PDCs but not
CD11cþ DCs or Mo-DCs express TLR9 and make high
Current Opinion in Immunology 2004, 16:21–25
22 Innate immunity
Figure 1
Pathogen
PAMPs
Tissue
PAMPs
MØ,
PMN
PAMPs
Cytokines
Cytokines, PAMPs
DC
Altered self
Altered self,
PAMPs
Cytokines
Conserved
pathogen
Antigens
Cytokines,
Cell contact
Cytokines,
Cell contact
NK cell
γδ T cell
NKT cell
γδT cell
Current Opinion in Immunology
Possible signals involved in innate dendritic cell activation. DCs could sense the presence of a potential pathogen via detection of PAMPs (exogenous
signals) or infection-induced alterations in self-markers (endogenous signals). Either type of signal may be detected by DCs directly or indirectly.
The indirect pathway involves inflammatory cytokines and other mediators produced by various cell types responding to the exogenous or
endogenous signals. In addition, DCs may present conserved pathogen antigens to gd or NKT cells bearing invariant T-cell receptors and receive
activation signals in return. Pathways are colour-coded according to the source of signal (red for pathogen, pink for tissue, green for NK/gd
T cell, brown for NKT/gd T cell, orange for dendritic cell and purple for macrophages (Mfs)/polymorphonucleocytes (PMNs). Receptors are not
indicated for the sake of clarity.
levels of IFN-a in response to synthetic CpG-containing
oligonucleotides (CpG ODNs; [9–11]). Murine PDCs
also use TLR9 to respond to CpG ODNs and viral
genomes bearing similar motifs [14]. As PDCs are
thought to be primarily involved in responses to viral
infection [15] it is, therefore, possible that the major
physiological role of TLR9 is viral DNA recognition.
In rat and mouse, however, TLR9 is also expressed by
non-plasmacytoid spleen DCs, which respond to CpG
ODNs by producing IL-12 (R Josien, unpublished; [16]).
In addition, murine PDCs show a broader TLR repertoire
than their human counterparts and express TLR4, as well
as most other TLRs [16,17]. Therefore, it would appear
that the distinctions in TLR repertoire among DC types
are not conserved across species, although it is possible
that this simply reflects the tissue origin of the cells,
namely blood in the case of humans versus secondary
lymphoid tissues in rodents. Nevertheless, in mice, as in
humans, particular DC subsets can be identified that lack
expression of specific TLRs. Thus, mouse spleen PDCs
selectively lack TLR3 and mouse spleen CD8aþ DCs do
not express TLR7 [16].
The engagement of TLRs on DCs leads to increased expression of MHC–peptide complexes and co-stimulatory
molecules, as well as the production of immunomodulaCurrent Opinion in Immunology 2004, 16:21–25
tory cytokines, all of which have a profound effect on
T-cell priming and differentiation [8]. It is important,
however, to note that some aspects of this process could
be secondary to TLR signalling. Hoshino et al. [18] have
reported that CD40 upregulation, commonly used as a
marker of DC activation, is markedly diminished in
murine DCs deficient for signal transducer and activator
of transcription (STAT)-1 or for the receptor for type I
interferons (IFN-I) after treatment with TLR4 or TLR9
agonists. This result suggests that full DC activation in
response to TLR signals may largely depend on production of IFN-I and establishment of an autocrine or
paracrine positive feedback loop. IFN-I injection into
mice similarly activates DCs and promotes adaptive immune responses to co-administered antigen [19,20]. As
IFN-I can be produced by virtually any cell type in vivo, it
is possible that the activation of DCs in response to
infection occurs largely indirectly (Figure 1). Indeed,
Matzinger and co-workers [20] have argued that ‘alarm’
signals produced by virally infected tissues are sufficient
to activate DCs and, consistent with that notion, recent
in vitro experiments show that keratinocytes exposed to
a mimic of viral double-stranded RNA (dsRNA) produce
cytokines that act on DCs to make them competent to
prime T helper 1 (Th1) differentiation [21]. Similarly,
before TLRs were discovered, the effects of LPS on DC
www.sciencedirect.com
Activation of dendritic cells Reis e Sousa 23
migration in vivo were attributed to TNF and IL-1 rather
than to a direct effect of the PAMP on DCs [22]. But, if
inflammation induced by PAMPs is sufficient to activate
DCs, why do these cells also express TLRs and, more
pointedly, what is the significance of the lack of TLR
expression by specific DC subtypes? The answer is
unclear at present but it is likely that direct PRR triggering, but not indirect activation, allows DCs to differentiate between classes of pathogen (R Spörri and C Reis e
Sousa, unpublished). Thus, the main function of DCexpressed PRRs may not be to activate DCs to become
immunogenic APCs, but, rather, to convey information
about the nature of the insult, thereby allowing DCs to
direct an appropriate class of immune response.
DCs can also be activated in response to the engagement
of PRRs other than TLRs. Sensing of dsRNA via protein
kinase R (PKR) has been recently described as a TLRindependent pathway for DC activation by viruses, illustrating the importance of cytosolic PRRs in innate viral
sensing [23]. Cytosolic PAMP detection may not be
restricted to viral infections as some members of the Nod
family of cytosolic proteins can acts as PRRs for components of bacterial peptidoglycans [24–27]. However, the
role of Nod proteins in DC activation has yet to be
reported. Other than TLRs, PKR and Nods, another
major class of PRRs regulating DC activation may be
C-type lectins. DC-SIGN, a C-type lectin, can signal in
response to Mycobacterium tuberculosis, synergising with
LPS to induce IL-10 production by Mo-DCs [28]. Dectin-1, another C-type lectin that acts as a PRR for bglucan, can transduce some signals independently of
TLRs in macrophages [29,30] and could play an important role in DC activation by yeasts. Other C-type lectins
expressed in DCs (e.g. blood dendritic cell antigen-2
[BDCA-2], dendritic cell immunoactivating receptor
[DCAR]; [31,32]) can also act as signalling receptors,
although their role in PAMP recognition has yet to be
established. In contrast, and despite some suggestions to
the contrary [33], some C-type lectins such as the mannose receptor may act simply as endocytic receptors,
concentrating potential pathogens for antigen presentation and recognition by bona fide PRRs.
PAMP-independent innate activation of dendritic cells
PAMPs and ‘PAMP surrogates’, such as inflammatory
cytokines, are major DC stimuli. Other triggers, however,
may be PAMP independent. Matzinger [34] proposed
that DC activation does not involve recognition of molecules derived from potential pathogens, but rather the
recognition of endogenous host-derived molecules
released by cells undergoing necrosis. Such endogenous
‘danger’ signals may, in some cases, mimic PAMPs and
act as ligands for PRRs, a possibility given most credence
by a recent report demonstrating the involvement of a
putative TLR in skin graft rejection in mice [35].
Similarly, hyaluran degradation products, fibronectin A,
www.sciencedirect.com
fibrinogen, heat shock proteins and b-defensins have all
been put forward as putative endogenous TLR ligands,
although the possibility that they contain traces of microbial contaminants has not been rigorously excluded
(reviewed in [36]). Other putative ‘danger’ signals may
not mimic PAMPs at all. These include ATP, acting via
purinergic receptors [37], and bradykinins, which can
activate murine DCs via bradykinin receptors, leading to
the production of IL-12 and the priming of Th1 responses
[38]. The significance of such ‘danger’ signals during
infection remains to be established (see also Update).
In addition to ‘danger’ signals and inflammatory cytokines, other alterations of the endogenous milieu may also
be sensed by DCs (Figure 1). For example, NKG2D
recognises stress-induced ligands often found in tumour
cells [39]. NKG2D signalling promotes the activation of
natural killer (NK) cells and gd T cells and it is, therefore,
conceivable that it could perform a similar function for
DCs. In the same way, other C-type lectins shared between NK cells, gd T cells and DCs may monitor the
expression of stress molecules on neighbouring cells. In a
further analogy with NK cells, DCs might also be able to
sense loss or alteration of self-markers normally expressed
by healthy cells. Siglecs, a family of sialic acid recognition
molecules, could potentially serve such a function [40].
Virtually nothing is known about the innate suppression of
DC activation, although the fact that DCs isolated from
tissues undergo ‘spontaneous’ ex vivo activation could be
interpreted to mean that they are no longer subject to
inhibitory signals from neighbouring cells or extracellular
matrix, rather than the more prevalent view that they have
received a positive activation signal.
Just as in the case of PAMPs, one should consider that any
mechanisms for sensing endogenous ‘danger’ signals or
alterations of self-markers may act on DCs only indirectly.
For example, changes in self-markers can trigger NK-cell
activation, which, in turn, can promote the activation of
DCs and lead to the priming of Th1 responses [41–44].
Similarly, DC presentation of an appropriate antigen to
NKT cells leads to feedback signals that can fully activate
DCs independent of previous TLR signalling [45].
These data strongly suggest that the surveillance of infection by other innate effector cells can translate into DC
activation and initiation of adaptive immunity (Figure 1).
Conclusions
Microbial components and inflammatory cytokines have
long been known to profoundly affect DC phenotype and
function. However, the pathways involved in infection
sensing by DCs still remain elusive. Recent advances in
our understanding of innate immunity, including the
molecular identification of PRRs (e.g. TLRs) and sensors
of altered self (e.g. NKG2D), and an increased awareness
of the role of inflammatory cytokines in promoting
acquired immunity (e.g. IFN-I), have opened the door
Current Opinion in Immunology 2004, 16:21–25
24 Innate immunity
to molecular studies of DC activation. At the same time, it
is becoming increasingly clear that DC activation is a flexible process that can result in distinct types of ‘effector
DC’ that can direct multiple forms of immunity and may,
in some cases, even lead to T-cell tolerance. The challenge at present is to establish how DCs interpret and
integrate multiple innate activation and inhibitory signals
and how they convey the result to the adaptive immune
system. Targeting the translation of innate into adaptive
information by DCs offers new perspectives for manipulating the immune system for clinical benefit.
Update
Recent work has demonstrated that uric acid released
from dying cells may act as a ‘danger’ signal that promotes
cross-priming [46].
Acknowledgements
I am grateful to members of the Immunobiology Laboratory, Cancer
Research UK, for discussions and critical review of the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
express different toll-like receptors and respond to different
microbial antigens. J Exp Med 2001, 194:863-870.
12. Kadowaki N, Antonenko S, Liu YJ: Distinct CpG DNA and
polyinosinic-polycytidylic acid double-stranded RNA,
respectively, stimulate CD11cS type 2 dendritic cell precursors
and CD11cR dendritic cells to produce type I IFN. J Immunol
2001, 166:2291-2295.
13. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B,
Giese T, Endres S, Hartmann G: Quantitative expression of
toll-like receptor 1-10 mRNA in cellular subsets of human
peripheral blood mononuclear cells and sensitivity to CpG
oligodeoxynucleotides. J Immunol 2002, 168:4531-4537.
14. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A: Toll-like receptor
9-mediated recognition of herpes simplex virus-2 by
plasmacytoid dendritic cells. J Exp Med 2003, 198:1-9.
The authors show that the herpes simplex virus-2 (HSV-2) triggers IFN-I
production by murine PDCs via TLR9, an activity attributable to CpG
motifs in the viral genome. Sensitivity to lysosomotropic drugs suggests
that recognition occurs in an endocytic compartment after internalisation
and uncoating of viral particles.
15. Colonna M, Krug A, Cella M: Interferon-producing cells: on the
front line in immune responses against pathogens. Curr Opin
Immunol 2002, 14:373-379.
16. Edwards AD, Diebold SS, Slack EMC, Tomizawa H, Hemmi H,
Kaisho T, Akira S, Reis e Sousa C: Toll-like receptor expression in
murine DC subsets: lack of TLR7 expression by CD8aR DC
correlates with unresponsiveness to imidazoquinolines.
Eur J Immunol 2003, 33:827-833.
17. Okada T, Lian ZX, Naiki M, Ansari AA, Ikehara S, Gershwin ME:
Murine thymic plasmacytoid dendritic cells. Eur J Immunol 2003,
33:1012-1019.
18. Hoshino K, Kaisho T, Iwabe T, Takeuchi O, Akira S: Differential
involvement of IFN-beta in Toll-like receptor-stimulated
dendritic cell activation. Int Immunol 2002, 14:1225-1231.
An important paper showing that TLR4 and TLR9 signalling may lead to
some aspects of DC activation indirectly, through the induction of IFN-I.
1.
Janeway CA Jr: Approaching the asymptote? Evolution and
revolution in immunology. Cold Spring Harb Symp Quant Biol
1989, 54:1-13.
2.
Reis e Sousa C: Dendritic cells as sensors of infection. Immunity
2001, 14:495-498.
3.
Ruedl C, Kopf M, Bachmann MF: CD8(R) T cells mediate
CD40-independent maturation of dendritic cells in vivo. J Exp
Med 1999, 189:1875-1884.
19. Le Bon A, Schiavoni G, D’Agostino G, Gresser I, Belardelli F,
Tough DF: Type i interferons potently enhance humoral
immunity and can promote isotype switching by stimulating
dendritic cells in vivo. Immunity 2001, 14:461-470.
4.
Manickasingham S, Reis e Sousa C: Microbial and T cell-derived
stimuli regulate antigen presentation by dendritic cells in vivo.
J Immunol 2000, 165:5027-5034.
20. Gallucci S, Lolkema M, Matzinger P: Natural adjuvants:
endogenous activators of dendritic cells. Nat Med 1999,
5:1249-1255.
5.
Muraille E, De Trez C, Pajak B, Brait M, Urbain J, Leo O:
T cell-dependent maturation of dendritic cells in response
to bacterial superantigens. J Immunol 2002, 168:4352-4360.
6.
Mailliard RB, Egawa S, Cai Q, Kalinska A, Bykovskaya SN,
Lotze MT, Kapsenberg ML, Storkus WJ, Kalinski P:
Complementary dendritic cell-activating function of CD8R
and CD4R T cells: helper role of CD8R T cells in the
development of T helper type 1 responses. J Exp Med 2002,
195:473-483.
21. Lebre MC, Antons JC, Kalinski P, Schuitemaker JH, van Capel TM,
Kapsenberg ML, De Jong EC: Double-stranded RNA-exposed
human keratinocytes promote Th1 responses by inducing a
Type-1 polarized phenotype in dendritic cells: role of
keratinocyte-derived tumor necrosis factor alpha, type I
interferons, and interleukin-18. J Invest Dermatol 2003,
120:990-997.
7.
Akira S: Mammalian Toll-like receptors. Curr Opin Immunol 2003,
15:5-11.
8. Reis e Sousa C: Toll-Like receptors and dendritic cells: for
whom the bug tolls. Semin Immunol 2004, in press.
A recent review of Toll-like receptors and DCs, which expands on several
of the topics discussed here.
9.
Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V,
Bals R, Giese T, Engelmann H, Endres S, Krieg AM et al.: Toll-like
receptor expression reveals CpG DNA as a unique microbial
stimulus for plasmacytoid dendritic cells which synergizes with
CD40 ligand to induce high amounts of IL-12. Eur J Immunol
2001, 31:3026-3037.
22. Roake JA, Rao AS, Morris PJ, Larsen CP, Hankins DF, Austyn JM:
Dendritic cell loss from nonlymphoid tissues after systemic
administration of lipopolysaccharide, tumor necrosis factor,
and interleukin 1. J Exp Med 1995, 181:2237-2247.
23. Diebold SS, Montoya M, Unger H, Alexopoulou L, Roy P, Haswell L,
Al-Shamkhani A, Flavell R, Borrow P, Reis e Sousa C: Viral
infection switches non-plasmacytoid dendritic cells into high
interferon producers. Nature 2003, 424:324-328.
A demonstration of TLR-independent activation of DCs by viral dsRNA via
cytosolic PRRs, including PKR.
24. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A,
Thomas G, Philpott DJ, Sansonetti PJ: Nod2 is a general sensor
of peptidoglycan through muramyl dipeptide (MDP) detection.
J Biol Chem 2003, 278:8869-8872.
10. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A:
Specialization and complementarity in microbial molecule
recognition by human myeloid and plasmacytoid dendritic
cells. Eur J Immunol 2001, 31:3388-3393.
25. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J,
Fukase K, Inamura S, Kusumoto S, Hashimoto M et al.: Host
recognition of bacterial muramyl dipeptide mediated through
NOD2. Implications for Crohn’s disease. J Biol Chem 2003,
278:5509-5512.
11. Kadowaki N, Ho S, Antonenko S, de Waal Malefyt R, Kastelein RA,
Bazan F, Liu YJ: Subsets of human dendritic cell precursors
26. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S,
Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S et al.:
Current Opinion in Immunology 2004, 16:21–25
www.sciencedirect.com
Activation of dendritic cells Reis e Sousa 25
An essential role for NOD1 in host recognition of bacterial
peptidoglycan containing diaminopimelic acid. Nat Immunol
2003, 4:702-707.
27. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M,
Viala J, Tedin K, Taha MK, Labigne A, Zathringer U et al.: Nod1
detects a unique muropeptide from gram-negative bacterial
peptidoglycan. Science 2003, 300:1584-1587.
28. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M,
Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y:
Mycobacteria target DC-SIGN to suppress dendritic cell
function. J Exp Med 2003, 197:7-17.
Mannosylated lipoarabinomannan from Mycobacterium tuberculosis is
shown to bind to human DC-SIGN rather than the mannose receptor, as
had been suggested in [33]. Binding suppresses the ability of DCs to
produce IL-12 in response to LPS and augments production of IL-10. This
is possibly the first demonstration that a C-type lectin can act as a
signalling PAMP receptor on DCs, with the caveat that the authors have
not excluded the possibility that the signal is mediated via a TLR. The
latter is critical in the light of the data in [29,30] suggesting that another
C-type lectin, Dectin-1, collaborates with TLR2.
29. Brown GD, Herre J, Williams DL, Willment JA, Marshall AS,
Gordon S: Dectin-1 mediates the biological effects of betaglucans. J Exp Med 2003, 197:1119-1124.
30. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM:
Collaborative induction of inflammatory responses by Dectin-1
and Toll-like receptor 2. J Exp Med 2003, 197:1107-1117.
31. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F,
Gunther G, Johnston I, Lanzavecchia A, Nagasaka T et al.: BDCA-2,
a novel plasmacytoid dendritic cell-specific type II C-type
lectin, mediates antigen capture and is a potent inhibitor
of interferon alpha/beta induction. J Exp Med 2001,
194:1823-1834.
32. Kanazawa N, Tashiro K, Inaba K, Miyachi Y: Dendritic cell
immunoactivating receptor, a novel C-type Lectin
immunoreceptor, acts as an activating receptor through
association with Fc receptor c chain. J Biol Chem 2003,
278:32645-32652.
33. Nigou J, Zelle-Rieser C, Gilleron M, Thurnher M, Puzo G:
Mannosylated lipoarabinomannans inhibit IL-12 production
by human dendritic cells: evidence for a negative signal
delivered through the mannose receptor. J Immunol 2001,
166:7477-7485.
37. Schnurr M, Then F, Galambos P, Scholz C, Siegmund B, Endres S,
Eigler A: Extracellular ATP and TNF-alpha synergize in the
activation and maturation of human dendritic cells.
J Immunol 2000, 165:4704-4709.
38. Aliberti J, Viola JP, Vieira-de-Abreu A, Bozza PT, Sher A,
Scharfstein J: Cutting edge: Bradykinin induces IL-12
production by dendritic cells: a danger signal that drives Th1
polarization. J Immunol 2003, 170:5349-5353.
39. Diefenbach A, Raulet DH: The innate immune response to
tumors and its role in the induction of T-cell immunity. Immunol
Rev 2002, 188:9-21.
40. Crocker PR: Siglecs: sialic-acid-binding immunoglobulin-like
lectins in cell-cell interactions and signalling. Curr Opin Struct
Biol 2002, 12:609-615.
41. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C:
Human dendritic cells activate resting natural killer (NK) cells
and are recognized via the NKp30 receptor by activated NK
cells. J Exp Med 2002, 195:343-351.
See annotation to [44].
42. Piccioli D, Sbrana S, Melandri E, Valiante NM: Contact-dependent
stimulation and inhibition of dendritic cells by natural killer
cells. J Exp Med 2002, 195:335-341.
See annotation to [44].
43. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G,
Trinchieri G: Reciprocal activating interaction between natural
killer cells and dendritic cells. J Exp Med 2002, 195:327-333.
See annotation to [44].
44. Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A,
Morel PA, Storkus WJ, Kalinski P: Dendritic cells mediate NK cell
help for Th1 and CTL responses: two-signal requirement for
the induction of NK cell helper function. J Immunol 2003,
171:2366-2373.
References [41–43] demonstrate that interactions between DCs and NK
cells can lead to the reciprocal activation of both cell types. Reference
[44] suggests that activation by NK cells allows DCs to prime Th1
responses. Together, these studies underscore the possible importance
of PAMP-independent indirect activation of DCs in response to infection
or other stresses.
35. Goldstein DR, Tesar BM, Akira S, Lakkis FG: Critical role of the
Toll-like receptor signal adaptor protein MyD88 in acute
allograft rejection. J Clin Invest 2003, 111:1571-1578.
An intriguing study, suggesting that allograft rejection involves innate
activation via a putative TLR.
45. Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman RM: Activation of
natural killer T cells by alpha-galactosylceramide rapidly
induces the full maturation of dendritic cells in vivo and thereby
acts as an adjuvant for combined CD4 and CD8 T cell immunity
to a coadministered protein. J Exp Med 2003, 198:267-279.
This paper shows that NKT cells can recognise a-galactosyl-ceramide
presented by CD1d on DCs. NKT-cell activation via the T-cell receptor
results in the delivery of feedback signals to the DCs that, in turn, promote
their activation. This is an interesting example of PAMP-independent
indirect DC activation, which could operate during infection in response
to DC presentation of conserved pathogen antigens recognised by NKT
cells and, possibly, gd T cells.
36. Beg AA: Endogenous ligands of Toll-like receptors:
implications for regulating inflammatory and immune
responses. Trends Immunol 2002, 23:509-512.
46. Shi Y, Evans JE, Rock KL: Molecular identification of a danger
signal that alerts the immune system to dying cells.
Nature 2003, 425:516-521.
34. Matzinger P: Tolerance, danger, and the extended family.
Annu Rev Immunol 1994, 12:991-1045.
www.sciencedirect.com
Current Opinion in Immunology 2004, 16:21–25