Molecular Mechanisms of Induction of Tolerant and Tolerogenic Intestinal Dendritic Cells in Mice

13 Pages·2016·1.51 MB·English

Hindawi Publishing Corporation
Journal of Immunology Research
Volume 2016, Article ID 1958650, 12 pages
http://dx.doi.org/10.1155/2016/1958650
Review Article
Molecular Mechanisms of Induction of Tolerant and
Tolerogenic Intestinal Dendritic Cells in Mice
AlexSteimleandJulia-StefanieFrick
UniversityofTu¨bingen,InstituteofMedicalMicrobiologyandHygiene,Elfriede-Aulhorn-Strasse6,72076Tu¨bingen,Germany
CorrespondenceshouldbeaddressedtoJulia-StefanieFrick;[email protected]
Received22October2015;Revised6January2016;Accepted17January2016
AcademicEditor:SilviaBeatrizBoscardin
Copyright©2016A.SteimleandJ.-S.Frick.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
Howdoesthehostmanagetotolerateitsownintestinalmicrobiota?Asimplequestionleadingtocomplicatedanswers.Inorderto
maintainbalancedimmuneresponsesintheintestine,thehostimmunesystemmusttoleratecommensalbacteriainthegutwhile
ithastosimultaneouslykeeptheabilitytofightpathogensandtoclearinfections.Ifthistenderequilibriumisdisturbed,severe
chronicinflammatoryreactionscanresult.Tolerogenicintestinaldendriticcellsfulfilacrucialroleinbalancingimmuneresponses
andthereforecreatinghomeostaticconditionsandpreventingfromuncontrolledinflammation.Althoughseveraldendriticcell
subsetshavealreadybeencharacterizedtoplayapivotalroleinthisprocess,lessisknownaboutdefinitemolecularmechanisms
ofhowintestinaldendriticcellsareconvertedintotolerogenicones.Herewereviewhowgutcommensalbacteriainteractwith
intestinaldendriticcellsandwhythisbacteria-hostcellinteractioniscrucialforinductionofdendriticcelltoleranceintheintestine.
Hereby,differentcommensalbacteriacanhavedistincteffectsonthephenotypeofintestinaldendriticcellsandtheseeffectsare
mainlymediatedbyimpactingtoll-likereceptorsignallingindendriticcells.
1.Introduction from these findings for the treatmentof chronic inflamma-
torydisordersofthegut:inflammatoryboweldiseases.
The mammalian intestinal immune system has to rise to
different challenges. On the one hand, it has to tolerate 2.IntestinalDendriticCells:Subsetsand
the intestinal microbiota consisting of commensal bacteria,
BiologicalFunctions
fungi,andothermicrobes,therebyprofitingfrombeneficial
bacterial metabolites and other advantages. On the other Dendritic cells (DCs) comprise a heterogeneous leukocyte
hand, pathogen induced infections of the intestine have to population of different developmental origin and with dis-
be cleared without spacious damage of the intestinal tissue. tinctsurfacemarkersandbiologicalfunctions.DCsoriginate
Since a loss of tolerance to the own microbiota causes from blood monocytes or a common DC progenitor in the
chronic inflammation of the gut, efficient sensing of the bone marrow under steady-state conditions. The differen-
intestinalhomeostasisiscrucialtoavoidpathophysiological tiation into DCs relies on local presence of GM-CSF [1].
immune responses. In this context, intestinal tolerogenic DCsingeneralareutterlyspecializedantigenpresentingcells
dendritic cells play a crucial role as key mediators for the (APCs)whichareabletoinduceavarietyofdifferentimmune
maintenance of the intestinal homeostasis. While the main responses.Theyarethemostimportantcelltypeconnecting
question “how does the host manage to tolerate its own theinnateimmunesystemwithadaptiveimmuneresponses
intestinal microbiota?” is pretty simple, the answer is not [2].DCspatrolalmostalllymphoidandnonlymphoidorgans
trivial. andmeldpropertiesoftheinnateandadaptiveimmunityand
Here,wewanttofocuson(1)themolecularmechanisms thereforelinkthesetwomechanisticallydistinctbranchesof
thatmightcontributetotheinductionoftolerogenicDCsin the immune system [3]. Furthermore, DCs play a pivotal
theintestineand(2)thepotentialclinicalapplicationsarising role in mediating a protective adaptive immunity against
2 JournalofImmunologyResearch
pathogens while maintaining immune tolerance to self- theirbiologicalfunctionandcellularoriginthantheirsurface
antigens. Their crucial role for mediating self-tolerance is markerexpression[11,12].Wewilladaptthissystem,butwe
confirmed by the observation that DC depletion leads to a will focus on DC subsets located in the intestine and add
lossofself-toleranceandresultsinmyeloidinflammationand latestfindingsondifferentsurfacemarkerexpressionamong
theinductionofautoimmuneprocesses[4]. these subsets [13]. In general, DCs derive from common
Thegut-associatedlymphoidtissue(GALT)isthelargest dendritic cell progenitors (CDP) which, in turn, develop
immune organ of the body. The GALT has to ensure that fromhematopoieticprecursorcells.CDPsmaydifferentiate
thereisadynamicbalancebetweenprotectiveimmunityby intoeitherpreplasmacytoidDCs(pre-pDCs)orprecommon
fighting pathogens and regulatory mechanisms to prevent DCs (pre-cDCs) precursor cells [20, 21]. Murine pDCs are
autoimmunity [5]. Since the GALT is constantly exposed characterized by PDCA1 expression and their development
to large amounts of luminal antigens like food metabolites, is dependent on the transcription factors BATF3 [22], ID2
foreignpathogens,andcommensalmicrobes,thisbalancehas [23], NFIL3 [24], E2-2 [25], and IRF8 [22]. Murine cDCs
tobewelladjustedinordertocreatehomeostaticconditions commonly express XCR1 and SIRP𝛼 [26] and need RelB
intheintestine.Dendriticcellsareherebythekeyplayersfor [27],RPBJ[28],andIRF4[29]fordifferentiation.Intestinal
maintainingintestinalhomeostasis[6].Theyarespreadout murinecDCsadditionallyexpressCD103andcanbefurther
intheconnectivetissueunderlyingtheepitheliallayerofthe subdivided into two ontogenetically different populations,
gut[7]. dependent on their surface expression of CD11b [30]. IRF4
+
isneededfortheCD11b lineageoftheseCD103-expressing
or CD103-nonexpressing conventional DCs [29, 31, 32].
2.1.MorphologicalDifferencesbetweenDCsandMacrophages
+ −
(MΦ) in the Murine Intestine. DCs belong to the group CD103 CD11b build up cDC subset 1 (cDC1) whereas
+ +
CD103 CD11b formsubgroupcDC2(seeFigure1).Oneof
of mononuclear phagocytes (MPs) with macrophages
(MΦ) being another cell type belonging to this group. themostimportanteventsforthemaintenanceofintestinal
Discrimination between DCs on one hand and MΦ on the homeostasisistheinductionofregulatoryTcells(Tregs)(see
below).BesidesTGF-𝛽,Tregformationisdependentonthe
other hand is still a matter of ongoing debate. However,
concerningintestinalDCsandMΦ,certainsurfacemarkers presenceofretinoicacid(RA)thatisproducedbydendritic
cells [33, 34]. But only DCs possessing retinaldehyde dehy-
andtranscriptionfactorshavebeenreportedtobeuniquely
drogenases(ALDHs)canconvertvitaminA-derivedretinol
expressed by only one of these two groups. In the murine
toRA.Therefore,ALDHisacrucialenzymeforasubsequent
intestine, surface proteins which are exclusively expressed
inductionofTregsandthuspromotionofintestinaltolerance
byDCsareCD103[8–10],CD26,andCD272[9]. However,
+
andhomeostasis.ItwasnotclearwhichCD103 DCsubset
CD103 is not expressed from every DC subset (see below)
+ +
isresponsibleforTreginduction,sincebothCD103 CD11b
[11–13]. A DC specific transcription factor is Zbtb46 [13].
+ −
andCD103 CD11b DCscanproduceRAandinduceTregs
The only MPs in the murine intestine that express the
in vitro [35, 36]. Meanwhile, it could be demonstrated
proteins CD14, MerTK [9, 14], F4/80, and CD64 [15] are
+ + −
intestinal MΦ. The widely used surface markers for DC- that each CD103 DC subset (CD11b versus CD11b ) can
be subdivided in an ALDH-expressing and a non-ALDH-
macrophage discrimination, CD11c and MHC-II, are not
+ +
useful to distinguish murine intestinal DCs from MΦ, expressing subset [35]. Therefore, both CD11b CD103 and
− +
CD11b CD103 DCsareabletoinduceaRA-mediatedTreg
sincebothproteinscan be expressed inDCormacrophage
formation.Thiswas initiallydemonstratedin skin-draining
subpopulations [13, 15–19]. The expression of CD11b and
MHC-II varies among DC and MΦ subpopulations [13]. lymphnodes[35],butJanelsinsetal.confirmedthepresence
+ + +/−
Therefore,theproteinexpressionpatternofmurineintestinal of CD103 CD11b ALDH DCs also in the murine cLP
+
DCs under steady state conditions can be summarized as [37].BothCD103 DCsubsetstogethermonitortheluminal
CD11c+CD103+/−CD11b+/−MHC-II+CD26+CD272+Zbtb46+ environmentintheintestine.NotonlyareCD103+DCsable
CD14−MerTK−F4/80−CD64−,whilethephenotypeofintesti- to induce Treg-mediated immune tolerance in the intestine
nal murine MΦ is CD11c+/−CD103−CD11b+/−MHC-II+/− buttheyarealsoabletopromoteTh17differentiationofna¨ıve
CD26−CD272−Zbtb46−CD14+MerTK+F4/80+CD64+. An- Tcells.Th17cellscontributetothemanifestationofautoim-
+ +
other distinctive feature between DCs and MΦ is the munediseases[38,39]andCD103 CD11b seemtobemore
−
migratoryandproliferationbehaviour.Ingeneral,intestinal efficientinTh17promotionthantheirCD11b counterparts
DCsareshort-lived,proliferatingmigratorycellswhileMΦ [36, 40]. It can be assumed that ALDH−CD103+CD11b+/−
aretissueresident,long-lived,andnonproliferating[13]. mightpromotethisTh17immuneresponse,butfinalevidence
ismissinguntilnow.
+
2.2.DCSubpopulationsintheIntestine. Asmentionedabove, Concerning their distribution in the intestine, CD103
−
dendritic cells do not comprise a homogenous cell popu- CD11b DCs are prominent in the colonic lamina propria
+ +
lation. Different ways to distinguish one DC from another (cLP), while CD103 CD11b DCs are mostly found in the
+ +
are published and popular. The most prominent approach LP of the small intestine [29]. Additionally, CD103 CD11b
to differentiate between distinguishable DC subsets is to DCsfromthemesentericlymphnodes(MLN)alsoexpress
focus on different expression of surface proteins, especially ALDH,whichis,surprisingly,abdicablefortheinductionof
CD103 and CD11b [12, 13]. However, Guilliams and van de TregssincealossofALDHactivityintheMLNdidnotaffect
Laar have recently proposed to distinguish DCs rather by Treginduction[29].Thismightsupportthehypothesisthat
JournalofImmunologyResearch 3
CDP
Pre-pDC Pre-cDC
BINDAF2TILF33 RRPelBBJ
E2-2
IRF8
SIRP𝛼
IRF4 IRF4
pDC
PDCA1+ CD103+CD11b− cDC1 CD103+CD11b+ cDC2 CD103−CD11b+ DC
ALDH+ ALDH− ALDH+ ALDH− CCR2+ CCR2−
CD103+CD11b− cDC1 CD103+CD11b− cDC1 CD103+CD11b+ cDC2 CD103+CD11b+ cDC2 CD103−CD11b+ DCCD103−CD11b+ DC
RA RA
Treg Th17? Treg Th17? Th17
Figure1:Ontogeneticdevelopmentofintestinaldendriticcellssubpopulations.AdaptedfromGuilliamsetal.[35]andexpandedbyfindings
fromScottetal.[13].Seetextfordetails.Commondendriticcellprogenitor(CDP),preplasmacytoiddendriticcell(pre-pDC),precommon
dendriticcell(pre-cDC),plasmacytoiddendriticcell(pDC),commondendriticcell(cDC),aldehydedehydrogenase(ALDH),regulatoryT
cell(Treg),retinoicacid(RA),andT-helper17cell(Th17).Arrowswithsolidlinesrepresentpublisheddata,andarrowswithbrokenlines
representspeculativehypotheseswithmissingfinalevidence.
ALDHactivityismoreimportantatotherintestinalsiteslike Anotherspecificproteinthatisexpressedexclusivelyby
thelaminapropriaofthesmallorlargeintestineforlaterTreg intestinalDCsandnotbyintestinalMΦornonintestinalDCs
inductionafterDCmigration. isSIRP𝛼[42,43].Itseemstobeessentialforthegenerationof
Recently, Scott et al. discovered an additional CD103- CD103+CD11b+ sincealossoffunctionofSIRP𝛼resultsina
negativeDCpopulationinthemurineintestine[13].Thereis decreaseofthisDCpopulationintheintestine,accompanied
+ + − +
aCD11c MHC-II CD103 CD11b cellpopulation,ofwhich by markedly reduced induction of Th17 immune responses
about 15% provide features of DCs like Zbtb64, CD26, understeady-stateandinflammatoryconditions[42].
and CD272 expression; they respond to Flt3L; they are In general, it is important to keep in mind that CD103
migratorycellsandlackmacrophagemarkerslikeF4/80and expression on DCs is not a marker for universal tolero-
CD64 [13, 41]. They could be shown to be derived from genicity, since (1) even CD103+ DCs can fail to induce
+
committedpre-DCsasareCD103 mucosalDCs[8].These tolerogenicityifALDHisnotexpressedand(2)atolerogenic
−
CD103 DCscanbefurthersubdividedintotwofunctionally environment can be established even in the absence of
distinct subpopulations dependent on their CCR2 expres- CD103+DCs[44].
+ + +
sion. CCR2 CD103 CD11b DCs are more efficient in Th17
induction than their CCR-negative counterparts and a loss 2.3. Locations of Intestinal DCs. The murine intestine is a
+ − +
of the CCR2 CD103 CD11b DCs leads to a defective Th17 multifarious habitat for DCs where distinct sites harbour
responseandthereforefailstoclearaCitrobacterinfectionin differentDCsubsets.AcommonfeatureofintestinalDCsdis-
vivo. tinguishingthemfromDCsfromothernonintestinaltissues
4 JournalofImmunologyResearch
is the expression of CD103, with the already mentioned role in maintaining intestinal homeostasis since Traf6−/−
exceptionofCCR2+/−CD103−CD11b+DCs,especiallyDCsin mice fail to maintain intestinal homeostasis mediated by
thesmallintestine(SI)andPeyer’sPatches(PP)inmesenteric a reduction of Tregs and an increase of T-helper 2 (Th2)
lymph nodes (MLN) and, with minor occurrence, in the cells,finallyresultinginamicrobiotacomposition-dependent
colonic lamina propria (cLP) [8, 29, 41, 43, 45]. DCs from inductionofcolonicinflammation[55].
nonlymph node tissues remain some days at their inherent
sitebeforemigratingtoneighbouringdraininglymphnodes
5.TheDifferentMaturationPhenotypesof
[35,46].
DendriticCells
3.AntigenSensingandSamplingby Thecapabilityofinitiatinganimmuneresponsedependson
IntestinalDendriticCells thecurrentDCmaturationstate.Usually,antigenencounter
results in rapid DC maturation which is characterized
Invading microorganisms are recognized by pattern recog- by efficient endocytosis and antigen processing. Further-
nition receptors (PRRs) on the DC surface. PRRs include more, upregulation of MHC-II and T cell costimulatory
toll-like receptors (TLRs), retinoic acid-inducible gene I- moleculeslikeCD40,CD80,andCD86enhancedexpression
like receptors (RLRs), and nucleotide-binding oligomeriza- ofchemokinereceptorsandthesecretionofproinflammatory
tion domain-like receptors (NLRs) [47, 48]. PRRs recog- cytokines like IL-1𝛽, IL-6, TNF𝛼, and IL-12 are part of
nizepathogen-associatedmolecularpatterns(PAMPs)[49]. DC maturation. These events influence and activate other
PAMPscompriseaheterogeneousclassofdifferentantigens, cellular components of an induced immune response like
that is, surface components of bacteria. One of the most MΦ,neutrophils,andespeciallyTcells[56].
prominentPAMPswhichusuallyinducesDCmaturationis
lipopolysaccharide(LPS),anintegralcellsurfacecomponent
5.1. Mature DCs (mDCs). Induction of DC maturation is
ofallGram-negativebacteria.Usually,dendriticcellsunderlie
accompanied by a loss of the capacity to take up and
the intestinal epithelium and therefore the connection to
process antigen [57]. However, they literally develop into
the colonic lumen is restricted. However, there are three
professional antigen presenting cells (APCs) indicated by
prominent ways how intestinal dendritic cells can sample
powerfulantigenpresentationtona¨ıveTcells[2],aswellasby
luminalantigens:(1)withparticipationofgobletcellswhich
theirabilitytomigratetosecondarylymphaticorganswhere
deliversolubleandpreferablylowmolecularweightantigen
theypresentantigenstoTcells.
toneighbouringDCs[50],(2)withthesupportofCX3CR1+
phagocytotic cells which can actively capture antigen fol-
lowedbytransporttoneighbouringDCsviatightjunctions 5.2. Immature DCs (iDCs). Immature DCs (iDCs) express
[51], and (3) a direct sampling by DCs that extend their lowamountsofMHC-IIandTcellcostimulatorymolecules.
dendritestowardsthelumenestablishingadirectconnection They tend to promote T cell anergy and to generate Tregs,
tothecoloniclumen[52]. with both effects being crucial for intestinal homeostasis
[58]. iDCs furthermore express high levels of PRRs with
whichtheymediatetherecognitionofpotentialantigensand
4.IntestinalDendriticCellsand
thereforetheirendocytosis[57].
theGutMicrobiota
CD103+ DCs are reported to sample mainly bacteria [52] 5.3. Semimature DCs (smDCs) and Tolerant DCs. The
in contrast to CX3CR1+ MΦ which also capture soluble definition of a semimature DC phenotype is less distinct.
proteins and fungi [51, 53]. This illustrates the relevance The most important property of smDCs uniting different
of the bacterial microbiota composition for intestinal DCs. definitions is the inability to induce a proinflammatory
InteractionofDCswiththegutmicrobiotacanoccurdirectly Th1 or Th17 response and to be nonresponsive, or in other
bysamplingbacterialantigenorbyinteractionwithbacterial words “tolerant,” towards subsequent maturation stimuli
metabolic products like short chain fatty acids (SCFAs). [59,60]withthelatterbeingthecriterionthatmediatesthe
SCFAs like butyrate can interact with the DC receptor tolerogenic functions of smDCs [60]. DC semimaturation
GPR109AwhichfinallyleadstoanIL-10mediatedinduction leadstoacertainexpressionofTcellactivationandacytokine
ofTregs[54].Sincenotallgutcommensalbacteriaproduce secretionpatternthatisdistinctfromtheonesofimmature
SCFAs,amicrobiotashiftleadingtodysbiosiscanprofoundly and mature DCs. The definite phenotype varies from one
affect immunologicalmechanisms in the intestine. Toll-like semimaturation inducing strategy to another. SmDCs
receptor (TLR) signalling in DCs also seems to be crucial that are generated by treating immature DCs with TNF𝛼
for the maintenance of intestinal homeostasis. Different display a phenotype that can be summarized as CD11c+
bacterial components bind to distinct TLRs on the surface MHCIIhiCD86hiCD80hiCD40loCD54+CD205hiCD25hiTNFlo
of DCs resulting in the activation of intracellular signalling IL-12p40loIL-10lo[61].Inductionofsemimaturationvialow-
cascades which leads to DC maturation or semimaturation dose LPS and subsequent dexamethasone treatment results
(see below) accompanied by secretion of pro- or anti- in CD14+CD1aloCD80hiCD86hiMHCIIhiIL-10hiTNFlo DCs
inflammatory cytokines. The TLT adaptor molecule TNF- [62]. We use a Gram-negative gut commensal, Bacteroides
receptorassociatedfactor6(TRAF6)seemstoplayapivotal vulgatus, to induce semimaturation and define the smDC
JournalofImmunologyResearch 5
Table1:Phenotypesofsemimaturedendriticcellsdependentonsemimaturationinducingagent.LPS(lipopolysaccharide),Dex(dexameth-
asone),andPSA(polysaccharideA);highexpression(hi),lowexpression(lo),intermediateexpression(int),andnotdetermined(n.d.).
Semimaturationinducingagent MHC-II CD40 CD80 CD86 IL-10 IL-6 TNF𝛼 IL-12 Source
B.vulgatus int lo lo lo n.d. int lo lo [59]
TNF𝛼 hi lo hi hi lo n.d. lo lo [61]
LPS+Dex hi n.d. hi hi hi n.d. lo n.d. [62]
B.fragilisPSA int n.d. n.d. n.d. hi n.d. n.d. n.d. [66]
ATP+LPS hi lo hi hi hi n.d. lo lo [120]
E.multilocularis lo n.d. n.d. lo int lo n.d. lo [121]
LowdoseLPS int lo lo lo n.d. int lo lo [64]
𝛼-1Antitrypsin int lo n.d. int hi lo n.d. n.d. [65]
phenotype as CD11c+MHCIIintCD40loCD80loCD86lo 6.TheRoleofDendriticCellsinInductionof
TNF𝛼loIL-12loIL-6int[59].Besidesthesestrategies,DCsem- InflammatoryBowelDisease(IBD)
imaturation can be induced by treating immature DCs
with ATP and LPS [63], low dose Salmonella LPS [64], 𝛼-1 The development of inflammatory bowel diseases (IBD)
antitrypsin[65],BacteroidesfragilisPSA[66],orEchinococcus withitstwomajorrepresentativesCrohn’sdisease(CD)and
multiloculariscellaggregates[67].Theresultingphenotypes ulcerativecolitis(UC)isassociatedwith(1)aninappropriate
concerning the most important immunomodulatory mole- immuneresponsetonormallybenignstimulilikecommensal
culesaresummarizedinTable1. microbes, (2) an inefficient clearance of microbes leading
to a continuous stimulation of the immune system, or (3)
5.4. Tolerogenic DCs. While mature DCs (mDCs) promote failingto turnfromanadequateproinflammatoryresponse
efficientinductionofinflammatoryimmuneresponses,iDCs toinflammationresolvinganti-inflammatoryimmunereac-
and smDCs fail to do so. They rather have the property tions[70].Inthiscontext,thecompositionoftheintestinal
to actively prevent from inflammatory reactions and are microbiotaisdecisivefortheonsetofcolonicinflammation
therefore also termed tolerogenic DCs (tolDCs). The term in most mouse models of experimental colitis [71] and
“tolerogenic” includes one, several, or all of the following intestinal DCs are crucial for driving immune responses in
features DCs must provide to be considered “tolerogenic”: either a proinflammatory or a rather homeostatic direction
(1) the induction of unresponsiveness of T cells, (2) active [72].Forexample,Il10−/−micedevelopchroniccolitiswhich
induction of Tregs, (3) inhibition of proinflammatory T resultsfromtheabsenceofsuppressionofMyD88-dependent
cell responses, and (4) promotion of T cell apoptosis or T commensal-inducedinflammationbyIL-10[73].
cell anergy [6]. In this context, the interplay between the Understeady-stateconditions,circulatingLy6Chimono-
intestinal epithelial cells and the host immune system is of cytes are repopulated into tolerogenic F4/80lowCD103+
essentialimportance. CD11c+ LP DCs, which contribute to homeostasis by sup-
Moregenerally,regulatoryortolerogenicDCskeeptheir
portingtolerogenicfunctions[16].Ontheotherhand,under
abilitytopresentantigens,butatthesametimetheydown- inflammatory conditions during colitis, Ly6Chi monocytes
regulatetheexpressionofTcellcostimulatorymoleculesand develop into CD103−CX3CR1intCD11b+ LP DCs, which
proinflammatorycytokinesbutinturnupregulateinhibitory
mediateinflammationduringcolitis[16].
molecules like PD-L1, CD95L, or IDO as well as anti-
inflammatorycytokinessuchasTGF-𝛽andIL-10[68].Fur- The tolerogenic functions of intestinal DCs are mainly
thermore,theyareresistanttoasecondmaturationinducing mediated by the induction of regulatory T cells (Tregs).
signal[68].Importantly,DCsalsoinfluencethedifferentia- As a characteristic feature, Tregs express the transcrip-
tionofna¨ıveTcellsintoTh1,Th2,Th17,orTregcells,mostly tion factor forkhead box P3 (Foxp3) [74]. Induction of
+ + +
due to supplying a certain cytokine environment [69]. In CD4 CD25 Foxp3 Tregs is essential for intestinal home-
a healthy individual, the presence of tolDCs is important ostasis [75] and a loss of Tregs leads to a fatal multiple-
and a loss of tolDCs can result in the development of AID organ-associatedautoimmunedisease[76].Tregsareusually
[4]. Semimature DCs are potent tolerant and tolerogenic convertedintheperipheralimmunesystemwiththehelpof
+
DCs since they fulfil many to all of the above-mentioned CD103 dendriticcells[77]whereuponthisTreginductionis
criteria,dependentontheagentwithwhichsemimaturation dependentonthepresenceofTGF-𝛽andretinoicacid(RA)
is induced. As already mentioned before, the main char- [78].
acteristic that makes semimature DCs tolerogenic is their However,duringcolitis,CD103−CXCR1intCD11b+DCs,
unresponsiveness(tolerance)towardssubsequentmaturating although also present under steady-state conditions, mas-
stimuli[59,64,65]. sivelyinfiltratethecolonicLPandmediateproinflammatory
6 JournalofImmunologyResearch
Treg
Intestinal
epithelial cell
TGF𝛽
CD47 IL-10
IL-10
LPS
SIRP𝛼 2
MyD88 TLR-4
wnt 1
JAK-2 ITRRAAKF46
PI3K
4 IL-10 TGF𝛽 IRAK1 MHC II
P STAT3
𝛽-catenin 5 mTOR
STAT3 H+ PSA
P IL-10 p38𝛼 V1 TLR-2
P 6 V0 7
+
H
3
𝛽-catenin TGF𝛽/ALDH1A2 Lysosome Gadd45𝛼
NF𝜅B p50
IFN𝛽/IL-𝛽/IL-18 p38
Intestinal
Nucleus
NF𝜅B p50 dendritic cell
Proinflammatory cytokines
Activation
Inhibition
Figure2:Possiblemolecularmechanismsoftoleranceinductioninintestinaldendriticcells.Thewhitenumbersinblackcirclesrefertothe
numberingofregulationmechanismsinthetext.Seetextfordetails.
immuneresponsesbyproducingIL-12,IL-23,iNOS,andTNF intestinalDCs.Allproposedmechanismsaresummarizedin
[16]. Figure2.
(1)Cell-to-Cell-ContactandSTAT3Signaling.Epithelialcells
7.PossibleMolecular Mechanismsof oftheintestineexpressthesurfaceproteinCD47whichcan
DCToleranceInductionintheIntestine directly interact with signal regulatory protein 𝛼 (SIRP𝛼)
expressedonthesurfaceofDCswhichunderlietheintestinal
Lessisknownaboutdefinedmechanismsoftoleranceinduc- epithelialcelllayer.Thisprotein-protein-interactionhasbeen
tioninintestinalDCs.However,knowledgeabouttolerance showntoresultinajanuskinase-2(JAK-2)dependentsignal
induction mechanisms of other DC subsets or of in vitro transducer and activator of transcription 3 (STAT3) activa-
generatedDCscanbetransferredtointestinalDCstoexplain tion downstream of SIRP𝛼 in DCs [79]. STAT3 activation,
howtheymanagetotolerateluminalbacterialorfoodanti- in turn, leads to enhanced IL-10 secretion from DCs and
gensandthereforepreventfromuncontrolledinflammatory therefore promotes tolerogenic properties in the intestinal
reactions.Here,wewanttopresentlatestresearchresultsand environment[79].STAT3haslongbeenknownasacrucial
discuss how and if these findings can be assigned also to negativeregulatorofimmunity.DisruptionofSTAT3leadsto
JournalofImmunologyResearch 7
alossofTcelltoleranceinmiceandefficientSTAT3signaling indoleaminedioxygenases(IDOs)anddecreasedexpression
isassociatedwiththeimmatureDCphenotype,generalIL- of proinflammatory cytokines like IFN𝛽, IL-1𝛽, and IL-18
10 secretion, and tolerance induction [80]. Therefore, not [91]. These implications for p50 in the induction of tolDCs
only does DC alone seem to be important for homeostasis aresupportedbythefindingthatp50-deficientDCsareweak
+
maintenance but also the “teamwork” with neighbouring inducersofaFoxp3 Tregdifferentiation[92].Formationof
epithelialcellsseemstocontributetotolerancemechanisms. p50-p50 homodimers contributes to LPS tolerance in MΦ
[93]andp50expressioninimmatureDCsiscrucialtoprevent
(2) IL-10 as a Central Cytokine for Intestinal Homeostasis. fromautoreactiveTcells[91].
Interleukin-10isakeyinhibitorycytokineinTcellactivation
and a mediator of intestinal homeostasis [81]. It is secreted (4) 𝛽-Catenin Promotes DC Tolerogenicity. 𝛽-catenin is a
byTcells,Bcells,andmostmyeloid-derivedcells[82].Mice transcription factor and part of the wnt signalling pathway.
lacking functional IL-10 or its IL-10R receptor counterpart It could be demonstrated that this signalling pathway with
spontaneouslydevelopsevereintestinalinflammation. the subsequent release of 𝛽-catenin into the nucleus results
Supporting the idea of IL-10 being a crucial mediator in the induction of tolDCs [94]. Gene expression profiles
for intestinal homeostasis [83]. Also humans with defec- ofintestinalLPDCsrevealedthatthissignallingpathwayis
tive mutations in the genes encoding for IL-10 or IL- decisivefortheDCtobecomeeithermatureortolerogenic.
10R develop a severe form of enterocolitis within the first 𝛽-catenin translocation into the DC nucleus resulted in
months after birth [84]. These observations made IL-10 a the expression of various tolerance-associated factors like
promising therapeutic candidate in order to treat chronic retinoicacid-metabolizingenzymes,IL-10andTGF-𝛽[94].
inflammatory conditions of the intestine. However, results
were not convincing since, in mice as well as in humans, (5)PreventionofV-ATPaseDomainAssemblyInducesTolero-
+
IL-10 administration did not ameliorate the inflammatory genic DCs. Vacuolar (H )-ATPases (V-ATPases) are ATP-
conditions [85]. IL-10 not only affects T cell responses but drivenprotonpumps.Theyarecomposedoftwodomains:a
can also provide autocrine and paracrine effects on DCs. peripheralV1domainandmembrane-embeddedV0domain
Since DCs express the IL-10 receptor (IL10R), IL-10 can [95].V-ATPasesareinvolvedinacidificationoflysosomesby
bind to IL10R resulting in a negative regulation of myeloid shufflingprotonsfromthecytosolintothelysosomiclumen
differentiationprimaryresponse88(MyD88)signalinginside [96]. The pH value of lysosomes is a crucial regulator for
DCs.MyD88isanadaptormoleculeofTLRsandisrequired theefficiencyofantigenprocessingsincelysosomalproteases
for downstream TLR signalling. IL-10/IL10R interaction being involved in antigen proteolysis require acidic envi-
mediates this negative regulation by a downregulation of
ronments [95]. The most important mechanism to regulate
interleukin 1 receptor associated kinase 4 (IRAK4) on the
lysosomalacidificationistocontroltheassemblyofthetwo
proteinlevelwithoutalteringIRAK4genetranscriptionrates
V-ATPase domains which is a required event for forming
[86].ItalsoleadstodissociationofMyD88fromTLRsand
a functional proton pump. It is known that activation of
subsequently promotes proteasomal degradation of IRAK1,
TLRs promotes domain assembly and therefore supports
IRAK4, and TRAF6, therefore silencing MyD88-dependent
DC maturation [96]. Domain assembly seems to be a PI-3
TLR signalling [86]. However, this is just the case if LPS as
kinaseandmTORmediatedeventsinceinhibitorysubstances
a TLR4 ligand is present at the same time to induce TLR
forbothmoleculescouldblockV-ATPasedomainassembly
signaling. IL-10 silencing of MyD88 signaling seems to be
andthereforepreventfromDCmaturationandpromotethe
crucial for the maintenance of intestinal homeostasis since
IL-10−/− micefailtodevelopintestinalinflammationifthese inductionofatolerogenicphenotype[95].Also,stimulation
of integrins and E-cadherins by cluster disruption of DC
micesimultaneouslylackMyD88[73].Asaconsequence,the
prevents from domain assembly and supports induction of
cytokineenvironmentdoesalsoaffectDCsintheirabilityto
atolerogenicphenotype[96,97].
inducetolerancemechanisms.
(3) NF𝜅B Signalling as a Mediator for Tolerogenicity. A key (6)p38𝛼ExpressionInfluencesExpressionofALDH1A2.MAP
kinases like ERK, JNK, and p38𝛼 form central pathways
regulator for DC maturation and inflammatory reactions
in general is NF𝜅B [87, 88]. NF𝜅B family members do that are activated by innate immune signals like PAMPs
[98,99]andexcessiveactivationofMAPkinasesarereported
not only have an activating potential for the induction of
proinflammatory cytokines. Two NF𝜅B proteins, p50 and to be associated with many autoimmune and inflammatory
p52,havebeenassociatedwithtranscriptionrepressionfunc- diseases [99]. However, the MAP kinase p38𝛼 provides a
tions and therefore induction of tolerance [89, 90]. Both dichotomicrole.Besidesbeinginvolvedinpromotingproin-
proteins lack the carboxyterminal transactivation domain flammatory responses, its activity seems also to be crucial
andcanforminhibitoryhomodimercomplexesthatprevent for the induction of a tolerogenic phenotype in intestinal
from transcription of proinflammatory genes. NF𝜅B p50 CD103+ DCs. In these DCs, p38𝛼 is constitutively active
has been shown to promote a tolerogenic DC phenotype and this activity is crucial for the expression of TGF-𝛽 and
by negatively affecting DC survival and their capacity to aldehyde dehydrogenase 1A2 (ALDH1A2), the latter being
efficiently activate T cells [91]. Accumulation of p50 in involvedinmetabolizingretinoicacid(RA).TGF-𝛽andRA
the nucleus of tolerogenic DCs can be accompanied by are involved in Treg generation and therefore promote gut
enhancedexpressionoftolerance-promotingmoleculeslike homingpropertiesofTcells[99].
8 JournalofImmunologyResearch
(7)Gadd45𝛼-MediatedTLR2SignallingContributestoTolero- DCs.Aswehavedemonstrated,differentcommensalbacteria
genic Features of Intestinal DCs. An abundant bacterial gut can have opposite effects on DC maturation. This makes
commensal,B.fragilis,isabletoprotectfromtheinductionof thecompositionofthemicrobiotadecisiveonwhetherDCs
EAEandexperimentalcolitisandincreasestheproportions mediatetolerogenicorinflammatoryLPS-triggeredimmune
+ +
of CD103 CD11c DCs [100, 101]. It could be demonstrated responses.
that this effect is mediated by polysaccharide A (PSA), an
immunomodulatorycomponentpresentinoutermembrane
8.PerspectivesforClinicalApproachesfor
vesicles derived from B. fragilis bacteria [66]. PSA pro-
theTreatmentofIBDUsingTolerantand
motesimmunologicaltolerancebyinducingIL-10producing
Foxp3+Tregsandprotectsanimalsfromexperimentalcolitis TolerogenicDendriticCells
[102]. The PSA caused induction of tolDCs is dependent
In order to be suitable as an administrable therapeutic,
on TLR2 and growth arrest and DNA-damage-inducible
45 𝛼 (Gadd45𝛼), since Gadd45𝛼-deficient DCs are unable tolerogenicDCs(tolDCs)havetobegeneratedinvitro.One
efficient way to induce tolDCs is coincubating them with
to mediate PSA-induced protection of experimental colitis
[66]. Gadd45𝛼 itself inhibits an alternative way of MAPK apoptoticcells.PhagocytosisofapoptoticcellsthroughDCs
p38-mediated signalling [103] and PSA-containing outer results in production of TGF-𝛽 which in turn contributes
membranevesiclesleadtoupregulationofGadd45𝛼[66]. to immune tolerance. Apoptotic cell-treated DCs efficiently
+ +
converted na¨ıve CD4 T cells into Foxp3 Tregs [108, 109].
Taken together, all of the mentioned molecular mech-
In general, apoptotic cell induced tolDCs are important for
anisms of tolerance induction in DCs are potentially able
inductionofimmunetolerance[110,111].Theyprovideupreg-
to take place in the intestine, either through participation
ulation of Galectin-1 and CD205 [112], two molecules that
of neighbouring intestinal epithelial cells or through direct
interactionofDCswithluminalcontent.Concerningluminal facilitate the manifestation of immune tolerance [113, 114].
content, bacteria and their PAMPs could promote all of At the same time, apoptotic cell treated DCs downregulate
the potential mechanisms via interaction with host pattern Gr-1andB-220[112],twomoleculestriggeringinflammatory
PRRs, especially TLRs. We identified apathogenic Gram- responses. These DCs furthermore downregulate the tran-
negative commensal strains, namely, Bacteroides vulgatus scription factor ROR𝛾t which is the decisive transcription
mpkandEscherichiacolimpk,mediatingcompletelycontrary factor for Th17 differentiation. Not only does treatment
effectsonDCmaturationand,inconsequence,theprogress with apoptotic cells lead to induction of tolDCs but also
of experimental colitis in mice [104, 105]. As mentioned treatment with herbal coumarins [115] and the macrocyclic
above,B.vulgatusinteractionwithimmatureDCsconverted antibioticrapamycin[116]leadstotolDCinduction.Invitro
themintoatolerantandtolerogenicsemimaturephenotype generated tolDCs have already been successfully used for
characterized by low to intermediate expression of MHC- the treatment of autoimmune disorders in animal models
II,CD40,CD80,andCD86,almostabsentsecretionratesof andperipheraltolerancecouldberestoredbyadministrating
TNF𝛼andIL-12p70,andremarkableIL-6secretion[59].As tolerogenicDCs[117].Approachestotreatautoimmunetype
acharacteristicoftolerantDC,thisphenotypecouldnotbe 1diabetesinamousemodelusingnonobesediabetic(NOD)
overcome with a subsequent maturating bacterial stimulus micewithtolerogenicDCswereverysuccessful[112].Todo
orbyCD40ligation[106].E.colimpkstimulation,however, so, apoptotic islet cells were used to induce DC mediated
resultedinefficientDCmaturation.Asaconsequence,E.coli tolerance against own islet cells [118]. All these applications
mpkcolonizationinexperimentalmousecolitisusingIl2−/− leadtothequestioniftransferoftolerogenicdendriticcells
mice resulted in colonic inflammation, a feature that could would also be an approach to treat IBD and, if yes, which
bepreventedbysimultaneousB.vulgatusmpkcolonization method to induce DC tolerance would be the method of
[104, 105]. We could prove that both bacteria differentially choice. A published approach for the treatment of Crohn’s
alterthephenotypeofdendriticcellsnotonlyinvitrobutalso disease patients is in vitro generation of DCs followed by
invivointhecolonicLPviaadjustedbacterialcolonization pulsingwithdexamethasone,proinflammatorycytokinesIL-
of the gut [105]. In this context, feeding B. vulgatus always 6,IL-1𝛽,andTNF𝛼,andPGE2[119].Concerningourfindings
induced tolerant and tolerogenic DC in the colonic LP. In that a certain gut commensal, B. vulgatus mpk, efficiently
anotherstudyusingdistinctE.colibacteriathatjustdifferin induces tolerant and tolerogenic DCs in vitro as well as in
the structure of their cell surface LPS, we could prove that vivo [59, 104, 105], we would recommend using host gut
theLPSstructurealonedecidesifLPDCsareconvertedinto commensalbacteriaforinvitrotolDCgeneration.Inorderto
amaturephenotypeandthereforepromoteinflammationor providemorepotentialluminalantigenspresentedbyMHC-
if they are converted into tolerogenic semimature DCs and IIoftolDCs,adefinedmixtureofcommensalbacteriacould
thusmaintainintestinalhomeostasis[107].AsLPSprimarily beused.Thiswouldenlargetheamountofantigenicpeptides
signals via TLR4, tolerance induction mechanisms where againstwhichtolerancewouldbeinduced.
NF𝜅B p50, Gadd45𝛼, MyD88-signaling, 𝛽-catenin, and/or
V-ATPase domain assembly are involved could be possible. Disclosure
Since LPS is a cell wall component of all Gram-negative
bacteria, the resulting abundance in the intestinal lumen Theauthorsdiscloseallcommercialaffiliationsandcompet-
could largely contribute to tolerance induction in intestinal ingfinancialinterests.
JournalofImmunologyResearch 9
ConflictofInterests identity and diversity of mouse tissue macrophages,” Nature
Immunology,vol.13,no.11,pp.1118–1128,2012.
The authors declare that there is no conflict of interests
[15] C.C.Bain,C.L.Scott,H.Uronen-Hanssonetal.,“Residentand
regardingthepublicationofthispaper. pro-inflammatory macrophages in the colon represent alter-
nativecontext-dependentfatesofthesameLy6Chimonocyte
Acknowledgments precursors,” Mucosal Immunology, vol. 6, no. 3, pp. 498–510,
2013.
WorkbyJulia-StefanieFrickwassupportedbytheDFG(DFG [16] A. Rivollier, J. He, A. Kole, V. Valatas, and B. L. Kelsall,
FR2087/6-1,DFGFR2087/8-1,CRC685,SPP1656),theDFG “InflammationswitchesthedifferentiationprogramofLy6chi
monocytes from antiinflammatory macrophages to inflam-
research training group 1708, the Bundesministerium fu¨r
matory dendritic cells in the colon,” Journal of Experimental
BildungundForschung(BMBF),andtheGermanCentrefor
Medicine,vol.209,no.1,pp.139–155,2012.
InfectionResearch(DZIF).
[17] F.Geissmann,S.Gordon,D.A.Hume,A.M.Mowat,andG.
J.Randolph,“Unravellingmononuclearphagocyteheterogene-
References ity,” Nature Reviews Immunology, vol. 10, no. 6, pp. 453–460,
2010.
[1] S.Rutella,G.Bonanno,L.Pierellietal.,“Granulocytecolony-
[18] D.A.Hume,“Differentiationandheterogeneityinthemononu-
stimulating factor promotes the generation of regulatory DC
clearphagocytesystem,”MucosalImmunology,vol.1,no.6,pp.
through induction of IL-10 and IFN-𝛼,” European Journal of
432–441,2008.
Immunology,vol.34,no.5,pp.1291–1302,2004. +
[19] O.Schulz,E.Jaensson,E.K.Perssonetal.,“IntestinalCD103 ,
[2] A.IwasakiandR.Medzhitov,“Regulationofadaptiveimmunity +
but not CX3CR1 , antigen sampling cells migrate in lymph
bytheinnateimmunesystem,”Science,vol.327,no.5963,pp.
and serve classical dendritic cell functions,” The Journal of
291–295,2010.
ExperimentalMedicine,vol.206,no.13,pp.3101–3114,2009.
[3] R.M.Steinman,“Decisionsaboutdendriticcells:past,present,
[20] M. Merad, P. Sathe, J. Helft, J. Miller, and A. Mortha, “The
and future,” Annual Review of Immunology, vol. 30, pp. 1–22,
dendriticcelllineage:ontogenyandfunctionofdendriticcells
2012.
andtheirsubsetsinthesteadystateandtheinflamedsetting,”
[4] C. Ohnmacht, A. Pullner, S. B. S. King et al., “Constitutive AnnualReviewofImmunology,vol.31,pp.563–604,2013.
ablationofdendriticcellsbreaksself-toleranceofCD4Tcells
[21] N.Onai,K.Kurabayashi,M.Hosoi-Amaikeetal.,“Aclonogenic
and results in spontaneous fatal autoimmunity,” Journal of
progenitorwithprominentplasmacytoiddendriticcelldevelop-
ExperimentalMedicine,vol.206,no.3,pp.549–559,2009.
mentalpotential,”Immunity,vol.38,no.5,pp.943–957,2013.
[5] K. J. Maloy and F. Powrie, “Intestinal homeostasis and its
[22] G.E.Grajales-Reyes,A.Iwata,J.Albringetal.,“Batf3maintains
breakdownininflammatoryboweldisease,”Nature,vol.474,no. autoactivationofIrf8forcommitmentofaCD8𝛼+conventional
7351,pp.298–306,2011.
DC clonogenic progenitor,” Nature Immunology, vol. 16, pp.
[6] S. Manicassamy and B. Pulendran, “Dendritic cell control of 708–717,2015.
tolerogenicresponses,”ImmunologicalReviews,vol.241,no.1,
[23] J. T. Jackson, Y. Hu, R. Liu et al., “Id2 expression delineates
pp.206–227,2011. differentialcheckpointsinthegeneticprogramofCD8𝛼+ and
[7] M.Gross,T.M.Salame,andS.Jung,“Guardiansofthegut— CD103+dendriticcelllineages,”TheEMBOJournal,vol.30,no.
murineintestinalmacrophagesanddendriticcells,”Frontiersin 13,pp.2690–2704,2011.
Immunology,vol.6,article254,2015.
[24] M. Kashiwada, N.-L. L. Pham, L. L. Pewe, J. T. Harty, and P.
[8] M.Bogunovic,F.Ginhoux,J.Helftetal.,“Originofthelamina B. Rothman, “NFIL3/E4BP4 is a key transcription factor for
propriadendriticcellnetwork,”Immunity,vol.31,no.3,pp.513– CD8𝛼+ dendriticcelldevelopment,”Blood,vol.117,no.23,pp.
525,2009. 6193–6197,2011.
[9] J. C. Miller, B. D. Brown, T. Shay et al., “Deciphering the [25] B.Cisse,M.L.Caton,M.Lehneretal.,“TranscriptionfactorE2-
transcriptional network of the dendritic cell lineage,” Nature 2isanessentialandspecificregulatorofplasmacytoiddendritic
Immunology,vol.13,no.9,pp.888–899,2012. celldevelopment,”Cell,vol.135,no.1,pp.37–48,2008.
[10] C. Varol, A. Vallon-Eberhard, E. Elinav et al., “Intestinal [26] S. Gurka, E. Hartung, M. Becker et al., “Mouse conventional
laminapropriadendriticcellsubsetshavedifferentoriginand dendriticcellscanbeuniversallyclassifiedbasedonthemutu-
functions,”Immunity,vol.31,no.3,pp.502–512,2009. ally exclusive expression of XCR1 and SIRP𝛼,” Frontiers in
[11] M.Guilliams,F.Ginhoux,C.Jakubzicketal.,“Dendriticcells, Immunology,vol.6,article35,2015.
monocytesandmacrophages:aunifiednomenclaturebasedon [27] L. Wu, A. D’Amico, K. D. Winkel, M. Suter, D. Lo, and K.
ontogeny,”NatureReviewsImmunology,vol.14,no.8,pp.571– Shortman,“RelBisessentialforthedevelopmentofmyeloid-
578,2014. related CD8𝛼- dendritic cells but not of lymphoid-related
[12] M. Guilliams and L. van de Laar, “A Hitchhiker’s guide to CD8𝛼+ dendritic cells,” Immunity, vol. 9, no. 6, pp. 839–847,
myeloid cell subsets: practical implementation of a novel 1998.
mononuclear phagocyte classification system,” Frontiers in [28] M.L.Caton,M.R.Smith-Raska,andB.Reizis,“Notch-RBP-J
Immunology,vol.6,article406,2015. signalingcontrolsthehomeostasisofCD8− dendriticcellsin
[13] C.L.Scott,C.C.Bain,P.B.Wrightetal.,“CCR2(+)CD103(−) thespleen,”TheJournalofExperimentalMedicine,vol.204,no.
intestinaldendriticcellsdevelopfromDC-committedprecur- 7,pp.1653–1664,2007.
sorsandinduceinterleukin-17productionbyTcells,”Mucosal [29] E.K.Persson,H.Uronen-Hansson,M.Semmrichetal.,“IRF4
Immunology,vol.8,pp.327–339,2015. transcription-factor-dependentCD103+CD11b+ dendriticcells
[14] E. L. Gautier, T. Shay, J. Miller et al., “Gene-expression pro- drivemucosalThelper17celldifferentiation,”Immunity,vol.
filesandtranscriptionalregulatorypathwaysthatunderliethe 38,no.5,pp.958–969,2013.
10 JournalofImmunologyResearch
+
[30] B.T.Edelson,K.C.Wumesh,R.Juangetal.,“PeripheralCD103 maintainTcellhomeostasisbutdonotaffectcommensalism,”
dendriticcellsformaunifiedsubsetdevelopmentallyrelatedto TheJournalofExperimentalMedicine,vol.210,no.10,pp.2011–
CD8𝛼+ conventional dendritic cells,” Journal of Experimental 2024,2013.
Medicine,vol.207,no.4,pp.823–836,2010. [46] N. S. Wilson, L. J. Young, F. Kupresanin et al., “Normal
[31] B.VanderLugt,A.A.Khan,J.A.Hackneyetal.,“Transcrip- proportionandexpressionofmaturationmarkersinmigratory
tionalprogrammingofdendriticcellsforenhancedMHCclass dendritic cells in the absence of germs or Toll-like receptor
IIantigenpresentation,”NatureImmunology,vol.15,no.2,pp. signaling,”ImmunologyandCellBiology,vol.86,no.2,pp.200–
161–167,2014. 205,2008.
[32] A. Schlitzer, N. McGovern, P. Teo et al., “IRF4 transcription [47] C.Qian,J.Liu,andX.Cao,“Innatesignalingintheinflamma-
+
factor-dependentCD11b dendriticcellsinhumanandmouse toryimmunedisorders,”CytokineandGrowthFactorReviews,
controlmucosalIL-17cytokineresponses,”Immunity,vol.38, vol.25,no.6,pp.731–738,2014.
no.5,pp.970–983,2013.
[48] O.TakeuchiandS.Akira,“Patternrecognitionreceptorsand
[33] W.W.AgaceandE.K.Persson,“HowvitaminAmetabolizing inflammation,”Cell,vol.140,no.6,pp.805–820,2010.
dendritic cells are generated in the gut mucosa,” Trends in
[49] J. Brown, H. Wang, G. N. Hajishengallis, and M. Martin,
Immunology,vol.33,no.1,pp.42–48,2012.
“TLR-signalingnetworks:anintegrationofadaptormolecules,
[34] J.A.Hall,J.R.Grainger,S.P.Spencer,andY.Belkaid,“Therole kinases,andcross-talk,”JournalofDentalResearch,vol.90,no.
ofretinoicacidintoleranceandimmunity,”Immunity,vol.35, 4,pp.417–427,2011.
no.1,pp.13–22,2011.
[50] J.R.McDole,L.W.Wheeler,K.G.McDonaldetal.,“Gobletcells
[35] M.Guilliams,K.Crozat,S.Henrietal.,“Skin-draininglymph +
deliverluminalantigentoCD103 dendriticcellsinthesmall
−
nodescontaindermis-derivedCD103 dendriticcellsthatcon-
intestine,”Nature,vol.483,no.7389,pp.345–349,2012.
+
stitutivelyproduceretinoicacidandinduceFoxp3 regulatory
[51] E.Mazzini,L.Massimiliano,G.Penna,andM.Rescigno,“Oral
Tcells,”Blood,vol.115,no.10,pp.1958–1968,2010.
tolerance can be established via gap junction transfer of fed
[36] T. L. Denning, B. A. Norris, O. Medina-Contreras et al., + +
antigens from CX3CR1 macrophages to CD103 dendritic
“Functional specializations of intestinal dendritic cell and
cells,”Immunity,vol.40,no.2,pp.248–261,2014.
macrophage subsets that control Th17 and regulatory T cell
[52] J. Farache, I. Koren, I. Milo et al., “Luminal bacteria recruit
responses are dependent on the T cell/APC ratio, source
+
CD103 dendriticcellsintotheintestinalepitheliumtosample
of mouse strain, and regional localization,” The Journal of
bacterialantigensforpresentation,”Immunity,vol.38,no.3,pp.
Immunology,vol.187,no.2,pp.733–747,2011.
581–595,2013.
[37] B. M. Janelsins, M. Lu, and S. K. Datta, “Altered inactivation
[53] A.Vallon-Eberhard,L.Landsman,N.Yogev,B.Verrier,andS.
of commensal LPS due to acyloxyacyl hydrolase deficiency
Jung,“Transepithelialpathogenuptakeintothesmallintestinal
in colonic dendritic cells impairs mucosal Th17 immunity,”
lamina propria,” Journal of Immunology, vol. 176, no. 4, pp.
Proceedings of the National Academy of Sciencesof the United
2465–2469,2006.
StatesofAmerica,vol.111,no.1,pp.373–378,2014.
[38] K. Honda and D. R. Littman, “The microbiome in infectious [54] N. Singh, A. Gurav, S. Sivaprakasam et al., “Activation of
diseaseandinflammation,”AnnualReviewofImmunology,vol. Gpr109a, receptor for niacin and the commensal metabolite
30,pp.759–795,2012. butyrate,suppressescolonicinflammationandcarcinogenesis,”
Immunity,vol.40,no.1,pp.128–139,2014.
[39] T.Korn,E.Bettelli,M.Oukka,andV.K.Kuchroo,“IL-17and
Th17cells,”AnnualReviewofImmunology,vol.27,pp.485–517, [55] D.Han,M.C.Walsh,P.J.Cejasetal.,“Dendriticcellexpression
2009. ofthesignalingmoleculeTRAF6iscriticalforgutmicrobiota-
dependent immune tolerance,” Immunity, vol. 38, no. 6, pp.
[40] K. Fujimoto, T. Karuppuchamy, N. Takemura et al., “A new
subsetofCD103+CD8𝛼+ dendriticcellsinthesmallintestine 1211–1222,2013.
expressesTLR3,TLR7,andTLR9andinducesTh1responseand [56] L. Delamarre, H. Holcombe, and I. Mellman, “Presentation
CTLactivity,”TheJournalofImmunology,vol.186,no.11,pp. of exogenous antigens on major histocompatibility complex
6287–6295,2011. (MHC) class I and MHC class II molecules is differentially
[41] V.Cerovic,S.A.Houston,C.L.Scottetal.,“IntestinalCD103− regulated during dendritic cell maturation,” The Journal of
dendritic cells migrate in lymph and prime effector T cells,” ExperimentalMedicine,vol.198,no.1,pp.111–122,2003.
MucosalImmunology,vol.6,no.1,pp.104–113,2013. [57] J.LiuandX.Cao,“Regulatorydendriticcellsinautoimmunity:
[42] C.L.Scott,T.F.P.Z.Murray,K.S.H.Beckham,G.Douce,andA. acomprehensivereview,”JournalofAutoimmunity,vol.63,pp.
M.Mowat,“Signalregulatoryproteinalpha(SIRP𝛼)regulates 1–12,2015.
+ +
thehomeostasisofCD103 CD11b DCsintheintestinallamina [58] M. V. Dhodapkar, R. M. Steinman, J. Krasovsky, C. Munz,
propria,”EuropeanJournalofImmunology,vol.44,no.12,pp. andN.Bhardwaj,“Antigen-specificinhibitionofeffectorTcell
3658–3668,2014. functioninhumansafterinjectionofimmaturedendriticcells,”
[43] E.K.Persson,C.L.Scott,A.M.Mowat,andW.W.Agace,“Den- JournalofExperimentalMedicine,vol.193,no.2,pp.233–238,
driticcellsubsetsintheintestinallaminapropria:ontogenyand 2001.
function,”EuropeanJournalofImmunology,vol.43,no.12,pp. [59] J. S. Frick, N. Zahir, M. Mu¨ller et al., “Colitogenic and non-
3098–3107,2013. colitogeniccommensalbacteriadifferentiallytriggerDCmat-
[44] S.Veenbergen,L.A.vanBerkel,M.F.duPre´etal.,“Colonictol- uration and Th cell polarization: an important role for IL-6,”
erancedevelopsintheiliaclymphnodesandcanbeestablished EuropeanJournalofImmunology,vol.36,no.6,pp.1537–1547,
independentofCD103+ dendriticcells,”MucosalImmunology, 2006.
2015. [60] M. B. Lutz, “Therapeutic potential of semi-mature dendritic
[45] N.E.Welty,C.Staley,N.Ghilardi,M.J.Sadowsky,B.Z.Igya´rto´, cellsfortoleranceinduction,”FrontiersinImmunology,vol.3,
and D. H. Kaplan, “Intestinal lamina propria dendritic cells article123,2012.