Plasmacytoid Dendritic Cells

170 Pages·2022·5.477 MB·English

by  Dipyaman Ganguly

Dipyaman Ganguly
Plasmacytoid
Dendritic
Cells
Plasmacytoid Dendritic Cells
Dipyaman Ganguly
Plasmacytoid Dendritic Cells
DipyamanGanguly
IICB-TranslationalResearchUnitofExcellence
CSIR-IndianInstituteofChemicalBiology
Kolkata,WestBengal,India
ISBN978-981-19-5594-5 ISBN978-981-19-5595-2 (eBook)
https://doi.org/10.1007/978-981-19-5595-2
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Preface
It has been more than 20 years that the plasmacytoid dendritic cells or pDCs were
established as a uniquely specialized immune cell and proposed to be a subset of
dendritic cells. Dendritic cells are the crucial interlocutors between the innate and
adaptive immune system. Accordingly, research over the past almost two decades
has revealed the functional dimensions of pDC as an innate-adaptive interlocutor,
quite like the conventional dendritic cells (cDCs), but distinct in its functional
scopes.Thereisanecessityforbringingtherichcorpusofknowledgeinthedomain
ina singlevolume,especially forprovidingaconsensus update fora newcomer in
thefield,aneedthatwasfeltbythepresentauthortoowhilebeingayounggraduate
studenthimself.Thepresentworkaimstofillthatgapinggap,beingperhapsthefirst
volumefocusedsolelyonscientificunderstandingabouttheplasmacytoiddendritic
cells and their role in orchestrating the immune response in different patho-
physiologiccontexts.
ResearchidentifyingpDCsastheprofessionaltypeIinterferonproducersinthe
body, with plausible affiliation to the dendritic cell lineage, interestingly went in
parallelwiththeresearcheffortsthatledtothediscoveryofcDCs.RalphSteinman
discoveredthecDCsinthelate1970sandestablishedthefunctionalphenotypesof
these cells over the following one decade along with other groups working in
different parts of the world. Possibility of a professional type I IFN producer, in
response to infectious agents, also cropped up from experimental data in the late
1970s.Theconcertedeffortbydifferentgroupsinlaboratoriesallaroundtheworld,
whichfinallyculminatedinidentifyingpDCsasadistinctdendriticcellsubset,was
phenomenalintermsofexperimentalconcurrences,incrementalinsights,andcross-
validations, and it took almost 20 years. The volume begins with the fascinating
story of these discoveries, citing the important experiments that provided the indi-
vidualpiecesofthepuzzle.Thisisfollowedbyabriefdescriptionofthemeticulous
developmental studies that traced the hematopoietic development of the two DC
subsets,confirminganontologicbasisforthesharedlineageaffiliationbycDCsand
pDCs as well as revealing an intricate transcriptional regulation for the individual
cellularidentities.
v
vi Preface
The major functional identity of pDCs, despite their ontogenic affiliation to the
DC lineage of professional antigen presenting cells, is the rapid and massive
induction of type I IFNs in response to activation of endosomal toll-like receptors
(TLRs) by pathogen-derived ligands. First, in a dedicated chapter, we will learn
about thespecializedmechanisms involvedinandpDC-intrinsicmolecularregula-
tors of TLR activation. Then we will follow it up with a discussion on the role of
pDCs,andtypeIIFNsreleasedbythem,indifferentcontextsofinfections,aswellas
inautoreactiveinflammation,aspDCshavebeenidentifiedoverthepastdecadeor
soasacrucialplayerinthepathogenesisofanumberofautoimmunediseasesaswell
aschronicinflammationassociatedwithmetabolicdisorders.
Next, a rather anti-inflammatory role, that pDCs are also widely documented to
play in varied clinical contexts, viz. allergic immune responses, graft versus host
diseases,andcancer,willbediscussed.RoleofpDCsindrivingimmunetoleranceis
identifiedtobedetrimentalinsuchclinicalcontexts.Finally,wewillconsiderhow
these diversified roles of pDCs in different contexts of immune response and
inflammation necessitate therapeutic targeting of pDCs also to suit the particular
contexts as we take stock of varied strategies adopted for targeting pDCs in such
discreetclinicalcontexts.PDCshavebeenoneoftheveryfewimmunecellsubsets
that areboth critically involved inthepathogenesisof various human diseasesand
amenable for therapeutic targeting with already proven efficacies in specific
contexts.
I hope the present monograph will serve its intended purpose of providing the
studentsandprofessionalsinterestedinthisdomainwiththenecessarybasicunder-
standingonthisveryinterestingmemberofourimmunesystem.Alargenumberof
researchgroupshaveputeffortsinthisdomainoverthepastfourdecadesproviding
withindispensableinsightsondifferentaspectsofthisveryimportantimmunecell.
Theobviousrestrictionsofspaceinthisvolumemighthavecausedanumberofsuch
effortsbeingomittedfromthelistsofcitations.Theauthorseekssincere apologies
forsuchomissions.
Idedicatethisvolumetoallmyresearchmentors,scientificcollaboratorsaswell
asmymentees,fromallofwhomIhadtheopportunitytolearnaboutthisextremely
interesting immune cell, during my research and academic career in cellular and
translationalimmunology.
Kolkata,WestBengal,India DipyamanGanguly
Contents
1 DiscoveryofaNewDendriticCellSubset. . . . . . . . . . . . . . . . . . . . . 1
1.1 ABriefBiosketchoftheImmuneSystem. . . . . . . . . . . . . . . . . . 1
1.2 DiscoveryoftheConventionalDendriticCells. . . . . . . . . . . . . . 2
1.3 TheSearchforaProfessionalInterferonProducer. . . . . . . . . . . . 4
1.4 ANewDendriticCellSubsetIsthe“ProfessionalInterferon
Producer”. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.5 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2 OriginandTranscriptionalIdentityofPlasmacytoidDendritic
Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.1 FLT3-ReceptorDependenceandSharedOriginofcDCs
andpDCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.2 MyeloidVersusLymphoidOriginofpDCs. . . . . . . . . . . . . . . . 12
2.3 TranscriptionalProgramforpDCCommitmentandFunction. . . . 14
2.3.1 E2-2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.3.2 IRF8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3.3 RegulatorsofFunctionalIdentity. . . . . . . . . . . . . . . . . . 17
2.4 LocalizationandMigrationofpDCs. . . . . . . . . . . . . . . . . . . . . 18
2.5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3 ActivationandFunctionsofPlasmacytoidDendriticCells. . . . . . .. . 25
3.1 Toll-likeReceptorActivationandSignalinginpDCs. . . . . . . . . 25
3.2 CellBiologyofEndosomalTLRLocalizationinpDCs. . . . . . . . 27
3.3 TheCytokineResponseinpDCsinResponsetoTLR
Activation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.4 AntigenPresentationbypDCs. . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.5 CellBiologyofDifferentialpDCResponsetoTLRActivation. . 33
3.6 CellularMetabolismofActivatedpDCs. . . . . . . . . . . . . . . . . . . 36
3.7 TheElusiveRoleofIL-3inpDCImmunobiology. . . . . . . . . . . . 38
vii
viii Contents
3.8 FunctionalHeterogeneityofPlasmacytoidDendriticCells. . . . . . 39
3.9 RegulatorsofTypeIIFNInductionbypDCs. . . . . . . . . . . . . . . 40
3.9.1 ILT7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.9.2 BDCA2.. . . . . . .. . . . . . .. . . . . . .. . . . . .. . . . . . .. . 41
3.9.3 Siglec-H. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.10 OtherRegulatorySurfaceMoleculesinpDCs. . . . . . . . . . . . . . . 43
3.11 EndocannabinoidsandCannabinoidReceptors. . . . . . . . . . . . . . 45
3.12 MetaboliteTransportersandReceptors. . . . . . . . . . . . . . . . . . . . 46
3.13 EffectofBiologicalSexonpDCActivation. . . . . . . . . . . . . . . . 46
3.14 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4 PlasmacytoidDendriticCellsandInfections. . . . . . . . . . . . . . . . . . . 61
4.1 RNAVirusesandpDCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4.2 HumanImmunodeficiencyVirusandpDCs. . . . . . . . . . . . . . . . 63
4.3 PDCsandtheNovelCoronavirusSARS-CoV-2. . . . . . . . . . . . . 66
4.4 DNAVirusesandpDCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.5 PDCsinBacterialInfections. . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.5.1 ExtracellularBacteriaandpDCs. . . . . . . . . . . . . . . . . . . 69
4.5.2 IntracellularBacteriaandpDCs. . . . .. . . . .. . . .. . . . .. 70
4.6 PDCsinMalaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.7 PDCsinFungalInfections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.8 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
5 PlasmacytoidDendriticCellsinAutoimmunity. . . . . . . . . . . . . . . . . 85
5.1 SystemicLupusErythematosus. . . . . . . . . . . . . . . . . . . . . . . . . 86
5.2 Psoriasis. . . . . .. . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . .. . 88
5.3 SystemicSclerosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
5.4 Sjogren’sSyndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
5.5 RoleofpDCsinOtherMajorRheumatologicalDisorders. . . . . . 94
5.6 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
6 PlasmacytoidDendriticCellsandMetabolicDisorders. . . . . . . . . . . 107
6.1 Type1DiabetesMellitus.. . . . .. . . . . .. . . . . .. . . . .. . . . . .. 108
6.2 ObesityandType2Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . 108
6.3 CardiovascularComponentsofMetabolicSyndrome. . . . . . . . . . 111
6.4 FattyLiverDiseaseandHepaticMetaflammation. . . . . . . . . . . . 112
6.5 APotentialPathogenicContinuumforAutoimmuneDiseases
andMetabolicSyndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
6.6 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Contents ix
7 TolerogenicFunctionsofPlasmacytoidDendriticCells. . . . . . . . . . . 121
7.1 ThymicpDCsandCentralTolerance. . . . . . . . . . . . . . . . . . . . . 122
7.2 MucosalToleranceDrivenbypDCs. . . . . . . . . . . . . . . . . . . . . . 123
7.3 TolerogenicpDCsandTissueTransplantation. . . . . . . . . . . . . . 125
7.4 SuppressionofAnti-cancerImmunity. .. . . . . .. . . . . .. . . . . .. 127
7.5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
8 PlasmacytoidDendriticCellsandCancer. . . . . . . . . . . . . . . . . . . . . 133
8.1 PlasmacytoidDendriticCellsandthe“Cancer-immunity
Cycle”. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
8.2 LeukemogenesisandpDCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
8.3 BreastCancerandpDCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.4 OvarianCarcinomaandpDCs. . . . . . . . . . . . . . . . . . . . . . . . . . 137
8.5 PDCsinNeoplasmasoftheAero-digestiveTract. . . . . . . . . . . . 137
8.6 MalignantMelanomaandpDCs. . . . . . . . . . . . . . . . . . . . . .. . . 139
8.7 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
9 TherapeuticTargetingofPlasmacytoidDendriticCells. . . . . . . . .. . 147
9.1 TargetingpDCsandTypeIIFNsinAutoreactive
Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
9.1.1 TargetingEndosomalTLRsinpDCs. . . . . . . . . . . . . . . . 147
9.1.2 BiologicsTargetingpDCsandTypeIIFNs. . . . . . . . . . . 151
9.2 TargetingpDCsinInfection. . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9.3 TargetingpDCsinCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
9.3.1 TargetingEndosomalTLRsandOtherpDC-intrinsic
Molecules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
9.3.2 PDC-BasedVaccinesforCancer. . . . . . . . . . . . . . . . . . . 154
9.4 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Chapter 1
Discovery of a New Dendritic Cell Subset
1.1 A Brief Biosketch of the Immune System
The immune system in the body of the higher animals, if not in all multicellular
organisms,providesforaspecializeddivisionoflabor,toacellortogroupsofcells
that,(a)performsentinelfunctiontolookforpotentialpathogensinvadingthebody
(in the context of infections) or transformed self-origin cells (in the context of
cancers),and(b)trytoneutralizetheplausible“danger”posedbysuchoccurrences
to the anatomic and physiological integrity of the body. Phylogeny has diversified
the cellular participants in this critical bodily function to two distinctive axes of
innateimmunityandadaptiveimmunityinhigheranimals.
The innate immune cells (e.g., neutrophils, macrophages, natural killer or NK
cells)performthesentinelfunctionaswellastakeupreflexivemitigatingmissions
throughreleaseof biochemical mediators orotherwise. The adaptive immune cells
(viz. T and B lymphocytes) expressing editable antigen receptors on their cell
surface, educate themselves with the molecular identity of the “danger,” be it
pathogens or transformed self-origin cells, and prepare for more efficient assault
on future encounters, by either working on their antigen receptors (e.g., the B cell
receptor or BCR) or selecting and expanding cellular clones expressing the most
relevantandefficientantigenreceptors(e.g.,incaseofTcellsexpressingspecificT
cellreceptorsorTCRs)orboth.
The decision taken by innate immune cells toget activated and initiate immune
response depends on a range of cell surface and cytosolic receptors expressed by
them, named the pattern recognition receptors or PRRs (viz. Toll-like receptors or
TLRs, RIG-I like receptors or RLRs, NOD-like receptors or NLRs, C-type lectin
receptors or CLRs). These receptors are neither selectable nor editable, unlike the
TCRs orBCRs,respectively,recognizemolecular patterns thatareofeitherpatho-
genic origin (the pathogen associated molecular patterns or PAMPs, e.g. bacterial
lipopolysaccharides,lipoproteins,flagellin,viralnucleicacids,etc.)orareknownto
signalvariousintracorporeal“danger”(the danger associated molecularpatterns or
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