Development and Function of Myeloid Subsets

321 Pages·2013·6.195 MB·2-323\321

by  Kenneth M. Murphy and Miriam Merad (Eds.)

ASSOCIATE EDITORS
K. Frank Austen
Harvard Medical School, Boston, Massachusetts, USA
Tasuku Honjo
KyotoUniversity, Kyoto,Japan
Fritz Melchers
University ofBasel, Basel, Switzerland
Hidde Ploegh
Massachusetts Institute of Technology, Massachusetts, USA
Kenneth M. Murphy
Washington University, St. Louis, Missouri, USA
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CONTRIBUTORS
CarlE.Allen
TexasChildren’sCancerCenter,andBaylorCollegeofMedicine,Houston,Texas,USA
GabrielleT.Belz
DivisionofMolecularImmunology,WalterandElizaHallInstituteofMedicalResearch,
andDepartmentofMedicalBiology,UniversityofMelbourne,Melbourne,Victoria,
Australia
Marie-LuiseBerres
DepartmentofOncologicalSciences,TischCancerInstitute,andImmunologyInstitute,
IcahnSchoolofMedicineatMountSinai,NewYork,USA
SilviaCerboni
InstitutCurie,andINSERMU932,Paris,France
MatthewCollin
InstituteofCellularMedicine,NewcastleUniversity,NewcastleuponTyne,United
Kingdom
MatteoGentili
InstitutCurie,andINSERMU932,Paris,France
FlorentGinhoux
SingaporeImmunologyNetwork(SIgN),AgencyforScience,TechnologyandResearch
*
(A STAR),Singapore
MuzlifahHaniffa
InstituteofCellularMedicine,NewcastleUniversity,NewcastleuponTyne,United
Kingdom
SteffenJung
DepartmentofImmunology,WeizmannInstituteofScience,Rehovot,Israel
MassimoLocati
HumanitasClinicalandResearchCenter,Rozzano,andDepartmentofMedical
BiotechnologiesandTranslationalMedicine,UniversityofMilan,Milan,Italy
NicolasManel
InstitutCurie,andINSERMU932,Paris,France
AlbertoMantovani
HumanitasClinicalandResearchCenter,Rozzano,andDepartmentofMedical
BiotechnologiesandTranslationalMedicine,UniversityofMilan,Milan,Italy
MiriamMerad
DepartmentofOncologicalSciences,TischCancerInstitute,andImmunologyInstitute,
IcahnSchoolofMedicineatMountSinai,NewYork,USA
AlexanderMildner
DepartmentofImmunology,WeizmannInstituteofScience,Rehovot,Israel
ix
x Contributors
KaawehMolawi
Centred’ImmunologiedeMarseille-Luminy,France,andMaxDelbrueckCenterfor
MolecularMedicine,Berlin,Germany
KennethM.Murphy
SchoolofMedicine,DepartmentofPathologyandImmunology,andHowardHughes
MedicalInstitute,WashingtonUniversity,St.Louis,Missouri,USA
ShalinNaik
TheWalterandElizaHallInstitute,Melbourne,Australia,andDivisionofImmunology,
TheNetherlandsCancerInstitute,Amsterdam,TheNetherlands
MeredithO’Keeffe
CentreforImmunology,BurnetInstitute,Melbourne,andDepartmentofImmunology,
MonashUniversity,Clayton,Australia
AndrewM.Platt
InstituteofImmunology,InfectionandInflammation,GlasgowBiomedicalResearch
Centre,UniversityofGlasgow,Glasgow,UnitedKingdom
GwendalynJ.Randolph
DepartmentofPathologyandImmunology,WashingtonUniversity,St.Louis,Missouri,
USA
PriyankaSathe
TheWalterandElizaHallInstitute,Melbourne,Australia,andImmunologyInstitute,
MountSinaiSchoolofMedicine,NewYork,USA
CyrilSeillet
DivisionofMolecularImmunology,WalterandElizaHallInstituteofMedicalResearch,
andDepartmentofMedicalBiology,UniversityofMelbourne,Melbourne,Victoria,
Australia
KenShortman
TheWalterandElizaHallInstitute,andCentreforImmunology,BurnetInstitute,
Melbourne,Australia
AntonioSica
HumanitasClinicalandResearchCenter,Rozzano,Milan,andDepartmentof
PharmaceuticalSciences,Universita`delPiemonteOrientale“AmedeoAvogadro”,
Novara,Italy
MichaelH.Sieweke
Centred’ImmunologiedeMarseille-Luminy,France,andMaxDelbrueckCenterfor
MolecularMedicine,Berlin,Germany
DavidVremec
TheWalterandElizaHallInstitute,Melbourne,Australia
SimonYona
DepartmentofImmunology,WeizmannInstituteofScience,Rehovot,Israel
CHAPTER ONE
Ontogeny and Functional
Specialization of Dendritic
Cells in Human and Mouse
Muzlifah Haniffa*,1, Matthew Collin*, Florent Ginhoux†,1
*
InstituteofCellularMedicine,NewcastleUniversity,NewcastleuponTyne,UnitedKingdom
†SingaporeImmunologyNetwork(SIgN),AgencyforScience,TechnologyandResearch
*
(A STAR),Singapore
1Correspondingauthor:e-mailaddress:[email protected];[email protected]
Contents
1. Introduction 2
2. HistoryofDCIdentificationandCharacterization 2
2.1 MouseDCs 2
2.2 HumanDCs 5
2.3 ClassificationofmouseandhumanDCs 8
3. RecentAdvancesinMouseDCImmunobiology:LessonsfromaRodent 9
3.1 OriginanddifferentiationofmouseDCs 9
3.2 CD8þ/CD103þDClineage 12
3.3 CD11bþDCs 14
3.4 PlasmacytoidDCs 16
3.5 Langerhanscells 17
3.6 InflammatoryDCs 18
4. RecentAdvancesinHumanDCImmunobiology 18
4.1 OriginanddifferentiationofhumanDCs 18
4.2 MyeloidCD141hiDCs 20
4.3 MyeloidCD1cþDCs 21
4.4 CD14þDCs 22
4.5 PlasmacytoidDCs 24
4.6 Langerhanscells 25
4.7 SlanDCs 26
4.8 InflammatoryDCs 27
5. HumanizedMice 27
6. MatchingMiceandMen 28
6.1 Interspeciesparallels 29
6.2 Interspeciesdifferences 32
7. TheRelationshipofDCstoMonocytesandMacrophages 33
8. NextStepsAhead 34
9. DisclosureStatement 35
Acknowledgments 35
References 35
AdvancesinImmunology,Volume120 #2013ElsevierInc. 1
ISSN0065-2776 Allrightsreserved.
http://dx.doi.org/10.1016/B978-0-12-417028-5.00001-6
2 MuzlifahHaniffaetal.
Abstract
Dendritic cells (DCs) are a heterogeneous group of functionally specialized antigen-
presenting cells that initiate and orchestrate immune responses. Our understanding
of DC immunobiology has been largely shaped by research using murine models.
TherelevanceofmurinefindingsonhumanDCorganizationandfunctionisonlyjust
beginning to be investigated. In this chapter, we present the key historical develop-
mentsandrecentadvancesinhumanandmouseDCresearchtocontextualizetheexis-
tingknowledgeonDCsubsetoriginandfunctionalspecializations.Wealsoproposea
frameworktoalignhumanandmouseDCnetworkstoenhanceourunderstandingof
theparallelorganizationofDCsinbothspeciesinordertofacilitatethefullexploitation
ofourknowledgeonDCbiologyandfunctionforclinicaltherapeuticstrategies.
1. INTRODUCTION
Dendritic cells (DCs) are a class of bone marrow (BM)-derived cells
found in the blood, lymphoid, interstitial, and epithelial tissues. DCs are
equipped with sensors to recognize pathogens, vaccines, and self-antigens;
process and present the relevant antigenic moieties to lymphocytes; and
direct the type, magnitude, and specificity of immune responses. Recent
advancesusingmurinemodelshavehelpedtodefineDCsasadistincthema-
topoieticlineageandtoseparatethemfromothermembersofthemononu-
clear phagocyte system (MPS), which also include blood monocytes and
tissue macrophages. Ontogeny and functional specializations of different
DC subsets in murine studies are beginning to be unraveled. However,
the translation of these findings to human biology remains uncertain. The
aim of this chapter is to present a framework to align human and mouse
DC networks to facilitate the full exploitation of current knowledge on
DC biology and function for clinical therapeutic strategies.
2. HISTORY OF DC IDENTIFICATION
AND CHARACTERIZATION
2.1. Mouse DCs
The capacity to generate diverse and specific responses to a wide range of
antigens,ahallmarkofthevertebrateimmunesystem,waswellrecognized
in thelate1950s(Burnet,1957).However,theinitiating eventsthatledto
antigenrecognitionbylymphocytespuzzledmanyresearchers.Thepursuit
toanswerthisimportantquestiongavebirthtothediscoveryofDCsbythe
OrganizationofHumanandMouseDendriticCells 3
late Nobel Laureate Ralph Steinman in the laboratory of Zanvil Cohn in
1973(Steinman&Cohn,1973).Thespleenwasknowntoharboraccessory
cellsimportanttoinitiateantibodyresponses.Investigationofspleencellsus-
pension identified a rare cell type (<1% of all adherent cells) with probing
morphology. These cells were structurally distinct from macrophages and
possessedpoorphagocyticcapacity.Theappearanceofbranchingstructures
when the live cells were viewed by phase contrast microscopy gave rise to
the name dendritic (from the Greek dendron, meaning tree) (Steinman &
Cohn, 1973). The evidence that DCs were indeed the principal initiator
of an immune response came several years later when they were shown
to be the critical component of accessory cells that stimulated mixed
leukocyte reaction (MLR) (Steinman & Witmer, 1978). Although MLR
wasausefultool,itdidnottestthespecificabilityofDCstoprocesscomplex
antigen and initiate an antigen-specific response. DCs were later shown
to be potent inducers of antigen-specific cellular and humoral im-
mune responses (Inaba, Steinman, Van Voorhis, & Muramatsu, 1983;
Nussenzweig, Steinman, Gutchinov, & Cohn, 1980). DCs were demon-
strated to present antigen using major histocompatibility complex (MHC)
Class II (MHC-II) molecules on their cell surface, but importantly, unlike
any other MHC-II-expressing cells, including macrophages and B cells,
DCswere theprincipal activator of na¨ıve T cells (reviewedin Steinman &
Nussenzweig,1980).
Splenic DCs were found to express MHC-II and the integrin CD11c
(Metlayetal.,1990;Steinman,Kaplan,Witmer,&Cohn,1979).Later,epi-
dermal Langerhans cells (LCs) were also noted to express MHC-II (Stingl,
Katz, Shevach, Wolff-Schreiner, & Green, 1978). Although Paul
Langerhans had identified LCs in human epidermis in 1868, they were
believed to be intraepidermal nerve endings due to their impregnation by
the neuronal label gold chloride (Langerhans, 1868). LCs were also found
to possess similar immunogenic functions as splenic DCs (Stingl, Katz,
Clement, Green, & Shevach, 1978). This led to the idea that DCs may
bemorewidespreadthanpreviouslyassumedandwasprovenbysubsequent
studies demonstrating the presence of DCs that constitutively express
MHC-IIintheinterstitialtissuesofthelung,heart,liver,thyroid,pancreas,
skin, kidney, ureter, and bladder but not brain (Hart & Fabre, 1981; Sertl
et al., 1986; Tse & Cooper, 1990).
DCs in peripheral tissues need to access lymph nodes (LNs) in order to
deliver antigen and interact with and activate na¨ıve T cells. LCs and inter-
stitial tissue DCs were shown to migrate through lymphatics to reach
4 MuzlifahHaniffaetal.
draining LNs (Balfour, Drexhage, Kamperdijk, & Hoefsmit, 1981; Kelly,
Balfour, Armstrong, & Griffiths, 1978). These early studies were followed
by parallel investigations on DC migration to the spleen and LN through
circulating blood (Austyn, Kupiec-Weglinski, Hankins, & Morris, 1988).
These studies, collectively, highlighted the importance of the lymphatics
asaconduitforperipheraltissueDCsandthebloodstreamasthemigratory
route for circulating antigen-loaded DCs to access the spleen and LN.
TheabilityofLCstomigratespontaneouslyfromtheepidermiscultured
in vitro led to the extensive use of this model to dissect the properties of
peripheralDCs(Larsenetal.,1990).Animportantfindingfromtheseearly
LC studies was the need for DCs to undergo phenotypic and functional
“maturation” to unleash their full immune-stimulating potential
(Schuler & Steinman, 1985). Immature DCs were effective at capturing
antigens,butmaturationisrequiredtoactivatelymphocytestothecaptured
antigens (Romani et al., 1989). A variety of maturation signals have been
studiedincludingmicrobialproducts(e.g.,lipopolysaccharide(LPS),flagel-
lin, and viral nucleic acids), endogenous molecules (e.g., HMGB1), cyto-
kines, and cell surface ligands recognizing receptors on DCs (CD40L).
The demonstration of a BM precursor origin for both splenic DCs and
LCs (Steinman, Lustig, & Cohn, 1974) also facilitated the development of
culture protocols to generate BM-derived DCs in vitro (Inaba et al., 1992).
CD8 (aa form) expression on a subset of resident splenic and thymic
DCswasthefirstdemonstrationthatDCswithinonetissuewerephenotyp-
(cid:2)
ically heterogeneous (Vremec et al., 1992). CD8 splenic DCs were later
defined by CD11b expression (Vremec & Shortman, 1997), and a further
þ
refinementtotheCD11b fractionwasmadebystudyingCD4expression,
þ (cid:2) (cid:2) þ
which divides splenic DCs into CD8 CD11b CD4 (CD8 DCs),
(cid:2) þ þ þ (cid:2) þ (cid:2)
CD8 CD11b CD4 (CD4 DCs), and CD8 CD11b CD4 (double-
negativeDCs)(Vremec,Pooley,Hochrein,Wu,&Shortman,2000).More
recently, high expression of endothelial cell-specific adhesion molecule
þ
(ESAM)wasshowntocharacterizeCD4 splenicDCs(Lewisetal.,2011).
Heterogeneity within interstitial nonlymphoid tissue (NLT) DCs
was first demonstrated by differential expression of CD103 in the gut
þ
(Annackeretal.,2005).ThelungCD103 DCtranscriptomewasalsonoted
to have high expression of the C-type lectin langerin, a marker initially
thought to be exclusive to LCs (Sung et al., 2006). The generation of
DC depletion models that were dependent on langerin expression con-
firmed that langerin was restricted not only to LCs but also on a subset of
dermal-andskin-drainingLNDCscoexpressingCD103anddistinct from
OrganizationofHumanandMouseDendriticCells 5
LCs (Bursch et al., 2007; Ginhoux et al., 2007; Poulin et al., 2007). NLT
DCsarenowbroadlydividedintotwosubsetscharacterizedbythemutually
exclusiveexpressionofCD103andCD11b(Ginhouxetal.,2009),exceptin
the lamina propria where an additional subset coexpressing CD103 and
CD11b can be found (Bogunovic et al., 2009).
The discovery of human plasmacytoid DCs (pDCs) (Grouard et al.,
1997;Siegaletal.,1999)promptedthesearchformurinepDCs,whichwere
identified in 2001 (Asselin-Paturel et al., 2001; Bjorck, 2001; Nakano,
þ þ
Yanagita, & Gunn, 2001). More recently, a CD8 CX3CR1 DC subset
related to pDCs was identified in mouse spleen (Bar-On et al., 2010).
Inadditiontosteady-stateDCsdescribedsofar,inflammationresultsin
theinfluxofdistinctpopulationsthatarepresumedtoarisefromcirculating
monocytes. There are two distinct types of murine “inflammatory DCs”
described. The first type was observed in the spleen of mice infected with
Listeriamonocytogenesandischaracterizedbytheproductionofvastquantities
ofTNF-aandiNOS(Tip-DCs)(Serbina,Salazar-Mather,Biron,Kuziel,&
Pamer,2003).Thesecondtype,identifiedmorerecently,wasfoundinthe
LN following LPS treatment (Cheong et al., 2010).
2.2. Human DCs
Thetwomostaccessiblehumantissuestostudyleukocytesaretheperipheral
blood and skin. This was in contrast to the lymphoid tissues (LTs), such as
the spleen and LN, as the early focus of murine DC studies. In 1982, the
searchforDCssimilartothoseofmouselymphoidorgansinhumanperiph-
eral blood identified a rare population of cells (<1% of mononuclear cells)
with cytological features as mouse DCs, expressing MHC-II and potent
allo-activators (Van Voorhis, Hair, Steinman, & Kaplan, 1982). Human
DCs express high levels of MHC-II (HLA-DR) and lack typical lineage
markers CD3 (T cell), CD19/20 (B cell), and CD56 (natural killer (NK)
þ (cid:2)
cell). The classical descriptions of DCs as HLA-DR lineage cells have
beenrefinedtoexcludemonocytesexpressingCD14andCD16butinclude
a number of positive DC lineage markers (Ziegler-Heitbrock et al., 2010).
Current nomenclature describes two myeloid DC subsets characterized by
the expression of CD1c/BDCA-1 and CD141/BDCA-3 in human peri-
pheral blood (MacDonald et al., 2002; Ziegler-Heitbrock et al., 2010).
Human epidermal LC was the first tissue DC to be described. LCs are
positive for CD36, ATPase, and FceR1 (reviewed in Romani,
Brunner, & Stingl, 2012). Intracellular tennis racket-shaped Birbeck
6 MuzlifahHaniffaetal.
granulesarevisiblebyelectronmicroscopy.LCsarenowidentifiedasCD1a
bright cells coexpressing the C-type lectin langerin, EpCAM, and
E-cadherin(reviewedinRomanietal.,2012).Thefirstdescriptionofder-
þ
mal DC was made in 1983 as a HLA-DR “indeterminate cell”
(Czernielewski, Schmitt, Faure, & Thivolet, 1983). In the early 1990s,
two dermal DC subsets characterized by the expression of CD1a and
CD14 were characterized (Lenz, Heine, Schuler, & Romani, 1993;
þ
Nestle, Zheng, Thompson, Turka, & Nickoloff, 1993). CD1a dermal
þþ
DCs distinct from CD1a epidermal LCs were identified from digested
dermalpreparations(Lenzetal.,1993).Studiesonspontaneouslymigrating
þ
cellsfromdermalexplantsculturedexvivoidentifiedthepresenceofCD14
þ
dermal DCs in addition to CD1a DCs (Nestle et al., 1993). Although
CD14hasbeenhistoricallyusedinhistopathologyanalysistoidentifymac-
þ
rophages,thespontaneousmigratorypropertyoftheCD14 cellsfromskin
þ
explantsresultedintheirclassificationasDCs.Insitu,theCD14 DCisnot
easily distinguishable from dermal macrophages (Zaba, Fuentes-Duculan,
Steinman,Krueger,&Lowes,2007),butflowcytometryofdermalcellsus-
pensionallowstheseparationofSSChiautofluorescentdermalmacrophages
þ
from CD14 DCs (Haniffa et al., 2009).
The different nomenclature used to define blood and tissue DCs has
madeitdifficulttounifythehumanDCnetwork.Werecentlyshowedthat
byusingthesameflowcytometryanalysisofbloodandcellsuspensionfrom
þ
theskin,liver,andlung,twomyeloidDCsubsetsidenticaltobloodCD1c
þ
and CD141 DCs can be identified in human peripheral tissues (Haniffa
þ
et al., 2012). In addition, human tissues also contain CD14 DCs, which
do not have a counterpart in peripheral blood (Haniffa et al., 2012). As
CD1a is an antigen expressed by interstitial DCs in human skin but not
þ
in other tissues and all dermal CD1a DCs coexpress CD1c (Haniffa
þ
etal.,2012;Zabaetal.,2007),wewillrefertothesecellsasCD1c migra-
tory DCs hereafter.
The logistical difficulties of studying primary human blood and tissue
DCswereeasedbythediscoveryintheearly1990sofinvitroDCgeneration
protocols from blood monocytes, using granulocyte macrophage colony-
stimulating factor (GM-CSF) and IL-4 (Romani et al., 1994; Sallusto &
þ
Lanzavecchia, 1994), and CD34 hematopoietic stem cells (HSCs) from
cord blood (Caux et al., 1996) and BM (Reid, Stackpoole, Meager, &
Tikerpae,1992),usingGM-CSFandTNF-a.Theseinvitroculturemodels
þ þ
allowedthegenerationoflargequantitiesofCD1a andCD14 DCsfrom