Lunqorbuns coll

Acivuod
Lunqorbuns
coll
Koruinocyo
Miqruory DC
Soll oido-
MHCcluss ll
MHCcluss ll
TCP
TCP
Tbymic
DCs
Tbymocyo
CD103

DC
CX
3
CP1

DC
CD103

CD103

DC
Pro-DC
To druininq
lymb nodo
8ATl3
lD2
lPl8
8ATl3
lD2
lPl8
lPl4
MDP
TPoq
coll
TPoq
coll
Monocyo
Monocyo
CDP CLP
lLT3L
lLT3L lLT3L
DC
DC
$.11&
$10'
/#4419
%CRUWNG
%QTVGZ
/GFWNNC
Lymboid
issuo-rosidon DCs
Pro-DC
Pro-DC
Pro-DC
CD80
or CD86
CD28 TCP
MHC
cluss ll lL-12
lL-18
lL-33
lL-4
lL-2S
T
H
1 coll
llN
5'%10.;/2*1+&6+557'
8lood
vossol
2CVVGTPTGEQIPKVKQPTGEGRVQTU
6.4U
'ZVTCEGNNWNCT 6.4U TLP1, TLP2, TLP4,
TLPS, TLP6, TLP10, TLP11
+PVTCEGNNWNCT 6.4U TLP3, TLP1, TLP8, TLP0
0.4U NOD1, NOD2, NLPP1, NLPP3,
NLPC4, NAlPS
4.4U PlG-l, MDAS, DHXS8 (LGP2)
%.4U CLLC18, CLLC4A(DClP), CLLC4C
(8DCA2), CLLC4L(minclo), CLLC4K
(lunqorin), CLLCSA, CLLC6A(docin2),
CLLC1A(docin1), CLLC0A(DNGP1),
CLLC10A(MGL1), CLLC12A(MlCL),
CLLC128, DC-SlGN(CD200), DLC20S
(CD20S), munnoso rocoors
&0#UGPUQTU AlM2, DAl, lll16
Dormul DC
Acivuod
dormul DC
CCP1
Sross siqnul
sucb us soll DNA
DC
Slin-rosidon
momory CD4

or CD8

T coll
To druininq
lymb nodo
Aniqon
llN
ln druininq lymboid
issuos, DCs induco nuivo
T colls o dioroniuo
ino lOXP3

T
Poq
colls.
Collulur immuniy
Poinoic
ucid,
TGl
Poinoic
ucid,
TGl
'RKFGTOKU
&GTOKU
Cyolinos
lood uniqons
und commonsul
bucoriu Mucus
Libolium
.COKPC
RTQRTKC
+06'56+0'
6*;/75
5-+0
+PVGUVKPCN
NWOGP
Tbymus-dorivod T
Poq

colls und inducod
T
Poq
colls muinuin
olorunco in issuo.
CX
3
CP1

DCs sumlo
luminul uniqons bu
uro non-miqruory in
bo soudy suo.
ln bo bymus, DCs romoo
conrul olorunco by doloinq
uuoroucivo bymocyos und by
romoinq T
Poq
coll dovolomon.
Circuluinq DCs muy
romoo olorunco o
oriborul issuo uniqons.
Liboliul coll-dorivod
lucors 'condiion'
CD103

DCs.
T
Poq
coll
OX40
T
H
2 coll
lL-4
Humorul immuniy
und ullorqy
lL-1
lL-6
lL-23
TGl
TGl T
H
11 coll
lL-21
lnummuion, uboqon
dolonco und issuo rouir
CD40 CD40L
lL-6
TCP
8CP
Anibody
lnlocod DC
MHC
cluss l
lL-21
lCOS
CXCPS
lCOS
lCOSL
lCOSL CD10
CD21
T
lH
coll 8 coll
CD8

T coll
CD8

T coll
Humorul immuniy
und 8 coll momory
&KTGEVRTGUGPVCVKQP
Dolonco uquins
inrucollulur uboqons
und umours
%TQUURTGUGPVCVKQP
Dolonco uquins
inrucollulur uboqons
und umours
CD103

DC
CD8

DC
Tissuo-dorivod
uniqon
CD8

CD8
-
UVliqb, ruumu,
irriuns, inlocion
CD103

DCs ulo
u inosinul
uniqons und
miqruo o druininq
lymboid issuos.
OX40L
lL-21
Lnvironmonul lucors sbuo DCluncions. lor
oxumlo, moubolios ol viumin Aund viumin D
condiion DCs o romoo CD4

und CD8

T coll
bominq o bo inosino or bo slin, rosocivoly.
T coll T coll
Slin bominq lnosino bominq
CCP10
Viumin D3
moubolios
Viumin A
moubolios
(roinoic
ucid)
CCP0
41
inoqrin
TPoq
coll
Poido
CD103

65.2
%'064#.61.'4#0%'
'(('%614+//70+6; &%&'8'.12/'06
6+557'+/24+06+0)
61.'4#0%'
S
u
p
p
l
e
m
e
n
t

t
o

N
a
t
u
r
e

P
u
b
l
i
s
h
i
n
g

G
r
o
u
p

Development
DCs differentiate in the bone marrow from macrophage and DC precursors (MDPs), which give rise to common DC precursors (CDPs) and monocytes. CDPs
subsequently differentiate into DC-restricted precursors (pre-DCs) and pDCs, although pDCs can also arise from common lymphoid progenitors (CLPs). Pre-
DCs circulate throughout the blood and differentiate into lymphoid tissue-resident CD8
+
and CD8

DCs
11
. In non-lymphoid tissues, the differentiation
of pre-DCs has been best studied in the intestine, where they give rise to CD103
+
CD11b
hi
and CD103
+
CD11b

DCs. Monocytes are the main precursors of

intestinal CD103

CD11b
+
CX
3
CR1
+
DCs in the steady state. Furthermore, monocytes differentiate into inflammatory DCs in most inflamed tissues.
Pre-DC differentiation into lymphoid tissue-resident CD8
+
DCs and non-lymphoid tissue-resident CD103
+
CD11b

DCs is dependent on the

transcription factors BATF3, ID2 and IRF8. However, CD103
+
CD11b
+
DCs and CD103

CD11b
+
DCs develop independently of these transcription
factors. The BATF3-dependent DC lineages show similar patterns of C-type lectin receptor (CLR) and Toll-like receptor (TLR) expression and also have
similar antigen-processing machinery
4
. A funtional equivalent of mouse BATF3-dependent DCs has been identified in human blood and in the spleen of
humanized mice; these cells are best characterized as BDCA3
+
XCR1
+
DCs
12,13
.
War and peace
In the steady state, DCs have crucial roles in maintaining
tolerance, not only to self antigen, but also to harmless
environmental antigens and commensal organisms.
However, DCs also continuously survey the tissue for signs
of danger (which they perceive using various pattern-
recognition receptors (PRRs)) and they initiate protective
adaptive immune responses following tissue damage and
infection. The panels below illustrate the role of DCs in
promoting a protective immune response in the skin and
in maintaining tolerance in the intestine. It is important
to state that DCs can promote effector or tolerogenic
immune responses in all tissues and the decision to initiate
war or peace is determined by numerous factors,
including the inflammatory status of the particular tissue.
Skin (left panel)
In the skin, DCs form a continuous cellular network and use PRRs to survey the tissue for foreign antigens that breach the barrier with
the external environment
2
. DCs in the epidermis (Langerhans cells) are developmentally and functionally distinct from dermal DCs,
which include the CD103
+
and CD11b
+
DC subsets. Skin-derived DCs constitutively migrate to draining lymph nodes; this process is
further increased in response to inflammatory signals.
Following skin injury, DCs become activated, modulating their chemokine receptor profile to facilitate their migration and
positioning in the draining lymph node, and upregulating their expression of MHC and co-stimulatory molecules and cytokines
3
.
Activated DCs promote the differentiation of naive antigen-specific T cells into effector T cell subsets
3
, and distinct DC populations
can be associated with different types of T cell response. For example, migratory CD103
+
DCs and lymphoid tissue-resident CD8
+

DCs show a superior ability to cross-present tissue-derived antigens and prime CD8
+
T cells
4
. Depending on the nature of the immune
challenge, DCs promote the differentiation of distinct effector CD4
+
T helper (T
H
) cell populations and drive the development of
Tfollicular helper (T
FH
) cells, which promote B cell antibody responses.
During inflammation, two additional subsets of DCs accumulate in the skin: monocyte-derived DCs and plasmacytoid DCs (pDCs).
Upon activation, pDCs secrete large amounts of IFN and initiate T cell responses against microorganisms
5
. Monocyte-derived DCs
can also participate in tissue immunity by initiating innate and adaptive immune responses against pathogens
6
.
Intestine (right panel)
Intestinal DCs must maintain tolerance to food
antigens and commensal bacteria, but are also crucial
for protective immunity against invading pathogens.
In the lamina propria, CD103

CX
3
CR1
+
CD11b
+
DCs
sample luminal antigens by projecting dendrites
through the epithelial cell layer
7
. CD103
+
CD11b
+

DCs migrate to the draining lymph nodes in a CCR7-
dependent manner and present intestinal antigens
to T cells; these DCs are potent producers of retinoic
acid and promote the peripheral differentiation
of regulatory T(T
Reg
) cells, which help maintain
gut integrity
8-10
. Retinoic acid-producing DCs
also imprint T cells with gut-homing molecules,
such as 47 integrin.
Dendritic cells: controllers
of adaptive immunity
Miriam Merad
Dendritic cells (DCs) are a heterogeneous population
of rare haematopoietic cells that co-evolved with
the formation of the adaptive immune system.
Distributed throughout the body, but most abundant
in lymphoid organs and at interface tissues, DCs are
constantly sampling their environment. Following
antigen uptake, they migrate to draining lymph
nodes to present tissue-derived antigens and initiate
adaptive immunity. DCs tailor adaptive immune
responses to match environmental cues, thereby
serving as a bridge between the innate and adaptive
immune systems. As such, they have key roles in
both initiating immune responses to pathogens and
maintaining tissue tolerance
1
. Remarkable progress
has been made in unravelling the intricacies of DC
biology and targeting these cells for therapy is
now a realistic goal
1
. This Poster summarizes key
DC functions, focusing on mouse DC subsets.
Abbreviations
AIM2, absent in melanoma 2; BATF3, basic leucine zipper
transcriptional factor ATF-like 3; BCR, Bcell receptor;
BDCA, blood DC antigen; CCR, CC-chemokine receptor;
CLEC, C-type lectin; CTL, cytotoxic T lymphocyte;
CXCR5, CXC-chemokine receptor 5; CX
3
CR1, CX
3
C-
chemokine receptor 1; DAI, DNA-dependent activator
of IFN-regulatory factor; DCIR, DC immunoreceptor;
DC-SIGN, DC-specific ICAM3-grabbing non-integrin;
DHX58, DEAH box protein 58; FLT3L, FMS-related tyrosine
kinase 3 ligand; FOXP3, forkhead box P3; ICOS, inducible
Tcell co-stimulator; ICOSL, ICOS ligand; ID2, inhibitor of
DNA binding 2; IFI16, interferon- inducible protein 16;
IFN, interferon; IL, interleukin; IRF, interferon regulatory
factor; MDA5, melanoma differentiation-associated gene
5; NAIP5, NLR apoptosis-inhibitory protein 5; NLR, NOD-
like receptor; NLRC, NOD-, LRR- and CARD-containing;
NLRP, NOD-, LRR- and pyrin domain-containing;
NOD, nucleotide-binding oligomerization domain;
RIG-I, retinoic acid-inducible gene I; RLR, RIG-I-like
receptor; TCR, Tcell receptor; TGF, transforming
growth factor-; TSLP, thymic stromal lymphopoietin;
XCR1, XC-chemokine receptor1.
Affiliations
MiriamMerad is at the Mount Sinai School of Medicine,
1425 Madison Avenue, New York 10044, USA.
email: miriam.merad@mssm.edu
The author declares no competing financial interests.
Edited by Yvonne Bordon and Olive Leavy; copyedited by
Isabel Woodman; designed by Simon Bradbrook.
2011 Nature Publishing Group. All rights reserved.
http://www.nature.com/nri/posters/dendriticcells
References available online.
IMMUNOLOGY