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Cells2021,10,1155.https://doi.org/10.3390/cells10051155www.mdpi.com/journal/cells
Review
ShapingofTCellFunctionsbyTrogocytosis
MasafumiNakayama*,ArisaHori,SaoriToyouraandShin‐IchiroYamaguchi
LaboratoryofImmunologyandMicrobiology,CollegeofPharmaceuticalSciences,RitsumeikanUniversity,
Shiga525‐8577,Japan;ph0137ie@ed.ritsumei.ac.jp(A.H.);ph0134ek@ed.ritsumei.ac.jp(S.T.);
ph0126kk@ed.ritsumei.ac.jp(S.‐I.Y.)
*Correspondence:mnakayam@fc.ritsumei.ac.jp;Tel.:+81‐77‐599‐3264
Abstract:Trogocytosisisanactiveprocesswherebyplasmamembraneproteinsaretransferredfrom
onecelltotheothercellinacell‐cellcontact‐dependentmanner.Sincethediscoveryoftheintercel‐
lulartransferofmajorhistocompatibilitycomplex(MHC)moleculesinthe1970s,trogocytosisof
MHCmoleculesbetweenvariousimmunecellshasbeenfrequentlyobserved.Forinstance,antigen‐
presentingcells(APCs)acquireMHCclassI(MHCI)fromallografts,tumors,andvirallyinfected
cells,andtheseAPCsaresubsequentlyabletoprimeCD8
+
Tcellswithoutantigenprocessingvia
thepreformedantigen‐MHCIcomplexes,inaprocesscalledcross‐dressing.Tcellsalsoacquire
MHCmoleculesfromAPCsorothertargetcellsviatheimmunologicalsynapseformedatthecell‐
cellcontactarea,andthisphenomenonimpactsTcellactivation.Comparedwithnaïveandeffector
Tcells,TregulatorycellshaveincreasedtrogocytosisactivityinordertoremoveMHCclassIIand
costimulatorymoleculesfromAPCs,resultingintheinductionoftolerance.Accumulatingevidence
suggeststhattrogocytosisshapesTcellfunctionsincancer,transplantation,andduringmicrobial
infections.Inthisreview,wefocusonTcelltrogocytosisandtherelatedinflammatorydiseases.
Keywords:acquisition;nibbling;stripping;cross‐dressed;cross‐presentation;dendriticcell(DC);
TCR;Treg;chimericantigenreceptor(CAR);fratricide;escapevariant
1.Introduction
Inordertocommunicatewitheachother,immunecellsexpressawidevarietyofcell
surfacemoleculessuchasreceptors,ligands,andadhesionmolecules.Cell‐cellcommuni‐
cationisrequiredforthegenerationofappropriateimmuneresponsestovariouspatho‐
gens.Ithasbeenestablishedthatduringcell‐cellinteractions,membrane‐associatedpro‐
teinsaretransferredbetweenimmunecells[1–4].Inthepastthisbiologicalphenomenon
hasbeencalledacquisition,nibbling,orstripping,andiscurrentlyreferredtoastrogocy‐
tosis,derivedfromtheancientGreekwordTrogo,meaning‘gnaw’[5].Incontrasttophag‐
ocytosis(PhagoistheGreekmeaning‘toeat’),whichisexecutedbyphagocytessuchas
macrophagesanddendriticcells(DCs),trogocytosisisconsideredtobeexecutedbyany
typeofcells,asdescribedbelow.Byacquiringmembrane‐associatedproteins,so‐called
recipientcellsgainalternativecellularfunctions.Incontrast,donorcellsmaylosethese
proteinsandcellularfunctions(Figure1).Inaddition,undercertainconditions,bi‐direc‐
tionaltrogocytosisisobserved[6](seeSection2).Insomecases,trogocytosismediatesthe
intercellulartransfernotonlyofplasmamembranesbutalsoofintracellularcontents[7,8],
whichmayalsoaltercellularfunctions.However,thispossibilityhasnotbeenextensively
investigated.
Thebestcharacterizedtrogocytosisinvolvesthetransferofmajorhistocompatibility
complex(MHC)moleculesfromantigen‐presentingcells(APCs)toTcellsduringtheir
interactions[1,3].TrogocytosisofMHCmoleculesshapesTcellfunctionsandisinvolved
invariousTcell‐mediateddiseases.Trogocytosishasbeenobservednotonlyinimmune
cellinteractions,butalsoduringepithelialcellcommunication[9]andinneuronalsynap‐
ses[10,11].Further,trogocytosisisusedbyamoebaetokillhostcells[12,13],indicating
Citation:Nakayama,M.;Hori,A.;
Toyoura,S.;Yamaguchi,S.‐I.
ShapingofTCellFunctionsby
TrogocytosisCells2021,10,1155.
https://doi.org/10.3390/cells10051155
AcademicEditor:RyutaKoyama
andKumikoNakada‐Tsukui
Received:3April2021
Accepted:6May2021
Published:10May2021
Publisher’sNote:MDPIstaysneu‐
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claimsinpublishedmapsandinstitu‐
tionalaffiliations.
Copyright:©2021bytheauthors.
LicenseeMDPI,Basel,Switzerland.
Thisarticleisanopenaccessarticle
distributedunderthetermsandcon‐
ditionsoftheCreativeCommonsAt‐
tribution(CCBY)license(http://cre‐
ativecommons.org/licenses/by/4.0/).
Cells2021,10,11552of16
thatthisbiologicalphenomenoniswidelyconservedthroughouteukaryotes.Recentfind‐
ingsoftrogocytosisinmicrobes[14],mammalianneuronalnetworks[15,16],andnon‐T
cellimmunecellinteractions[2,17,18]havebeenwellsummarizedbyotherspreviously
andalsointhisissue.Thus,herewemainlyfocusonTcelltrogocytosisandrelateddis‐
eases.
Figure1.Principalmodelsoftrogocytosis.Whentwotypesofcellsmakephysicalcontactviareceptor‐ligandinteractions,
thedrivingforceforinternalizationofreceptorsexpressedononecell(herecalledrecipient)co‐optsligand‐containing
plasmamembranefragmentsfromtheothercell(herecalleddonor).Notonlyarereceptorsandligandsinvolvedinthis
process,butadhesionmoleculesalsoplayarole.Thedonorcellslosemembranemoleculesandtheircellularfunctions,
whereastherecipientcellsgaindonor‐derivedmembranemoleculesandfunctions.Itisunclearhowdonor‐derivedmol‐
eculesexistonrecipientcells.ThethreehypothesizedmodelsareshownasA,B,andC.
2.PossibleMechanismsUnderlyingTrogocytosis
Themolecularmechanismsunderlyingtrogocytosisarenotfullyunderstood.How‐
ever,trogocytosisoftheTcellreceptor(TCR)andMHCreceptorligandpairhasbeen
extensivelycharacterized.Ofnote,Martinez‐Martinetal.haveshownthatTcellsacquire
MHCclassI(MHCI)fromAPCsthroughtheactionofsmallGTPasessuchasRhoGand
TC21[19].RhoGisknowntobeinvolvedinphagocytosis[20],andthustrogocytosisis
characterizedasincompletephagocytosis.Indeed,PI3KinhibitorseffectivelyinhibitTCR
trogocytosis[19,21].Likewise,naturalkiller(NK)cellsexpressingNKG2D,anNKactivat‐
ingreceptor,acquireligands,includingRaeI,MICA,andMICB,fromtumorcellsviaa
PI3K‐dependentpathway[22].Takentogether,trogocytosisappearstobeaccompanied
byrecipientcellreceptorinternalization(Figure1).
Donorcellsmayactivelyreleasetheirmembranefragmentstorecipientcells.These
membranefragmentsmayincludeextracellularvesicles(EVs)[23].Choudhurietal.have
shownthatTCRsignalingleadstosecretionofTCR‐enrichedmicrovesiclesviathecentral
supramolecularactivationcluster(c‐SMAC)[24].SortingofTCRtothec‐SMACandthe
productionofEVsisdependentontumorsusceptibilitygene101(TSG101),anessential
Cells2021,10,11553of16
componentoftheendosomalsortingcomplexrequiredfortransport(ESCRT)‐I[25].These
EVsaretransferredtoandactivateneighboringBcells[24].Ontheotherhand,Kimetal.
havereportedthatTCRsignalingcausesTCR‐enrichedmicrovilliparticles,calledTcell
microvilliparticles(TMPs),whicharetransferredtoandactivateneighboringDCs[26].
Interestingly,uponTCRstimulation,microvilliprovideastructuralplatformforTCR
clusteringwhereTSG101andthearrestindomain‐containingprotein1(ARRDC1)colo‐
calize,andTCRclustersarereleasedfromTcellsbytheprocessoftrogocytosis[26].The
authorsproposethatTCR‐enrichedEVs[24]mightalsooriginatefrommicrovilli[27].
Takentogether,thesestudiesrevealthat,duringT‐APCinteractions,TCRsignalingleads
notonlytoMHCtrogocytosisbutalsotosecretionofTCR‐enrichedEVs.Byendpoint
analysis,thisseriesofeventswouldbeviewedasbidirectionaltrogocytosis.EVswerealso
recentlyobservedtobereleasedfromcytotoxicTlymphocytes(CTLs)totargettumorcells
uponTCRactivation[28].Thus,theintercellulartransferofTCRsdescribedbelowmay
bemediatedbyEVs.
Innonimmunecells,TSG101andARRDC1arealsoinvolvedinformationandrelease
ofmicrovesicles,whicharecalledARRDC1‐mediatedmicrovesicles(ARMMs)[29].In
contrasttoexosomes,ARMMsaregeneratedattheplasmamembrane[30].Inaddition,
onecelloftwoconnectedcellsisreportedtoengulfthegapjunctiontotakeupmembrane
andcytosolofitsneighboringcells,whichiscalledaconnexosome[31].Thesephenomena
maybeportionsoftrogocytosisduringnonimmunecellinteractions.
Itisstillunclearhowdonor‐derivedproteinsexistonrecipientcells(Figure1).The
detectionofdonorproteinsonrecipientcellsbyflowcytometryraisesthefollowingpos‐
sibilities.Donormembranefragmentsmaybemerelyattached(modelA)orfused(model
B)torecipientcells.Alternatively,donor‐derivedproteinsmaybere‐expressedonrecipi‐
entcellsafterbeinginternalizedandrecycled(modelC),asproposedinacommentarticle
[32].ElectronmicroscopyshowedthatahumanNKcelllineacquiredAPCplasmamem‐
branefragments,whichwerenotfusedtobutratherlooselyattachedtotheplasmamem‐
branesoftheseNKcells[33].SimilarmorphologywasobservedonCD4+Tcellsthatac‐
quiredAPCplasmamembranefragments(datanotshown,butdiscussed[34]).Astudy
usingbotharatTcellsubclonesynthesizingMHCIIandanothersubclonewithacquired
MHCIIfromAPCsshowedthatonlytheformersubclonewassensitivetoanti‐MHCII
antibody‐mediatedcomplementlysis.Thus,thissuggeststheAPC‐derivedmembrane
fragmentsaremerelyattachedtoTcells[35].Takentogether,thesereportssupportmodel
A(Figure1)inwhichdonor‐derivedreceptorsnolongertransmitanysignalinrecipient
cells.Incontrast,somestudiesshowedthatdonor‐derivedreceptorsarefunctionalonre‐
cipientcells.Forinstance,inaco‐cultureoftwoCD8+Tcellclones,oneCD8+Tcellclone
hasbeenobservedtoacquireTCRfromtheotherTcellcloneandsubsequentlylysetarget
tumorcellsintheacquiredTCR‐restrictedmanner,suggestingthatthedonorTCRisfunc‐
tionalonrecipientTcells[36].ItwasalsoreportedthatNKcellsacquireCCR7,achemo‐
kinereceptor,fromdonorcells.Further,theseNKcellsgainedmigrationactivity,suggest‐
ingthatCCR7isfunctionalonrecipientNKcells[37].ThesestudiessupportmodelBor
C(Figure1);however,theintracellularsignalingdownstreamofacquiredreceptorshas
notbeeninvestigated.
IrrespectiveofwhethermodelA,B,orCiscorrect,donor‐derivedligands(MHC,
costimulatorymolecules,etc.)areprobablyfunctionalonrecipientcells.Indeed,numer‐
ousstudieshaveshowndonor‐derivedMHConrecipientcellsplaysimportantrolesin
acquiredimmunityasdescribedinthefollowingsections.
Cells2021,10,11554of16
3.Tumor
3.1.PrimingofCD8+TCellsbyCross‐PresentationandCross‐Dressing
CTLsplayanimportantroleinanti‐tumorimmunity.Todevelopanti‐tumorCTLs,
DCspresenttumorantigenswithMHCItonaïveCD8+Tcells[38–40].DCsarelargely
dividedintoconventionalDCs(cDC)andplasmacytoidDCs(pDCs)[41].pDCsareama‐
jorproduceroftypeIinterferon(IFN‐I)inresponsetoviralinfectionwhereascDCsare
themostpotentAPCs[41–43].ThecDCsarefurthersubdividedintoDCtype1cells
(DC1s)andDCtype2cells(DC2s)[41].DC2spresentextracellularantigensonMHCII
throughtheconventionalantigenpresentationpathwaywhereascDC1sareabletopre‐
sentextracellularantigensnotonlyonMHCII,butalsoonMHCI,calledcross‐presenta‐
tion(Figure2)[39–41].Ingeneral,asobservedinDC2s,extracellularantigensarepro‐
cessedandloadedonMHCIIinphagosomes.InDC1s,however,extracellularantigens
arereleasedfromphagosomestothecytosolandthentranslocatedviaTAP(transferas‐
sociatedwithantigenprocessing)moleculestotheendoplasmicreticulum(ER)whereex‐
tracellularantigenpeptidesaswellasintracellularantigenpeptidesareassociatedwith
MHCI[44,45].Regardingtheunusualpathwayofextracellularantigensfromphagosomes
tocytosol,ithasbeenrecentlyreportedthatDNGR‐1(alsoknownasCLEC9A)senses
necroticcell‐derivedF‐actin[46,47]anditshemITAM‐Syksignalinginducesphagosomal
membranerupturetoallowendocytosedantigenstoenterthecytosolinDC1s[48].
Inadditiontothecross‐presentationpathway,severalrecentstudieshavereported
thecross‐dressingpathway,inwhichDCsacquireMHCImoleculesfromneighboring
DCsortumorcells(Figure2).TheseMHCI‐dressed(cross‐dressed)DCsactivateCD8+T
cellsviathepreformedantigenpeptide‐MHCIcomplexeswithouttheabove‐mentioned
antigenprocessing[3,49,50].Priortothefirstdemonstrationofthecross‐dressingpathway
byDolanetal.[51],thetumor‐derivedexosomescontainingMHCIwerepreviouslycon‐
sideredtoprovokeanti‐tumorimmunity[52,53].Inthisstudy,whenFVBmouse(MHC
haplotype:H‐2q)bonemarrow‐derivedDCs(BMDCs)wereco‐culturedwithdyingH‐2b
tumorcellsexpressingovalbumin(OVA),theH‐2qBMDCsacquiredtheOVApeptide‐H‐
2KbcomplexesfromtumorcellsandsubsequentlyactivatedCD8+TcellsfromOT‐Imice
specificforOVAresidues257–264onH‐2Kb.Thus,thisindicatesthatBMDMsdonotuse
self‐MHC,butinsteadusenon‐selfMHCmoleculestoactivateTcells.Itshouldbemen‐
tionedherethatBMDCsareCD11c+MHCII+cellsgeneratedwithGM‐CSF;however,these
invitro‐culturedDCsarenotequivalenttoinvivoDCsandareneitherDC1snorDC2s
[54].Toaddresstheroleofcross‐dressedDCsinvivo,theauthorsusedCD11c‐diphtheria
toxinreceptor(DTR)transgenicBALB/c(H‐2d)miceinwhichDCsareremovablebydiph‐
theriatoxin(DT)treatment[55].InthesemiceinoculatedsubcutaneouslywithH‐2btumor
cellsexpressingOVA,OT‐ICD8+Tcellsvigorouslyproliferated,aneffectabolishedby
DTtreatment,indicatingthatDCsareessentialforOT‐ICD8+Tcellproliferationinre‐
sponsetothetumorcell‐derivedOVApeptide‐H‐2Kbinvivo[51].Subsequently,cross‐
dressinghasbeendemonstratedtobeinvolvednotonlyincancer[56–58],butalsoin
transplantationandduringmicrobialinfections(seeSections4.1and5).
Dependingonexperimentalconditions,cross‐dressinghasbeenshowntobecon‐
ductedbybothDC1sandDC2s.Further,DC1sarereportedlyessentialforcross‐dressing
ofDNAvaccineantigens[59,60]whereasDC2sshowhighercross‐dressingofneighbor‐
ingDC‐derivedMHCI[61–63].Thisapparentdiscrepancymaybeascribedtothediffer‐
enceintypeofdonorcellsthatDCsacquireMHCIfrom.InadditiontocDCs,pDCsalso
acquireantigen‐MHCcomplexesfromtumorcellsandstimulateMHC‐restrictedTcell
proliferation[64].Interestingly,arecentstudyhasshownthatpDCsgivetheantigen‐
MHCIcomplexestoDC1s,whichcontributetocross‐dressing[60].
Cells2021,10,11555of16
Figure2.TrogocytosisinTcellprimingandeffectorphases.Duringtheprimingphase,dendriticcell(DC)type2cells
(DC2s)presentextracellulartumorantigensonMHCIItoactivateCD4
+
TcellswhereasDCtype1cells(DC1s)areableto
presentthemonMHCI,calledcross‐presentation,toactivateCD8
+
Tcells.Inaddition,DC1sand/orDC2sacquirepre‐
formedantigen‐MHCIcomplexesforantigenpresentationtoCD8
+
Tcells,whichiscalledcross‐dressing.Inthecytotoxic
Tlymphocyte(CTL)effectorphase,CTLsstripofftargetantigensfromtumorcells.TheseCTLswithacquiredtumor
antigen‐MHCIarethenlysedbytumor‐unexperiencedCTLsthroughaprocesscalledfratricidecelldeath.Ontheother
hand,tumorcellsloseantigens,resultingingenerationofCTLescapevariants.
3.2.MHCTrogocytosisintheCTLEffectorPhase
TrogocytosisisalsofrequentlyobservedintheCTLeffectorphase.WhenCTLsattack
tumorcells,theyacquireMHCIfromtumorcells(Figure2)[7,65].However,itisstillun‐
derdebatewhethertrogocytosisenhancesorsuppressesCTLactivity.Giventhepositive
correlationbetweencytotoxicactivityandtrogocytosisability[66,67],CTLswithhigh
avidity(highrecognitionefficiency)mayexertbothhighcytotoxicityandtrogocytosisac‐
tivity.Alternatively,giventhattheacquiredantigen‐MHCcomplexeshavebeenproposed
totransmitsustainedTCRsignalsinCD4
+
Tcells[67–70],trogocytosismayprolongCTL
activation.Incontrast,aregulatoryfunctionoftheMHConCTLshasbeenalsoreported.
Forinstance,CTLsthathaveacquiredthetumorantigen‐MHCcomplexarerecognized
andlysedbytumor‐unexperiencedCTLs,whichiscalledfratricidecelldeath(Figure2)
[7,65,71].Likewise,itwasrecentlyreportedthattrogocytosis‐mediatedfratricideofchi‐
mericantigenreceptor(CAR)Tcellscausestumorescape[72](seeSection3.3).
ItisnoteworthythatTCR‐mediatedtrogocytosisstripstumorantigensfromtarget
tumorcells,causingantigenlossandtumorescape(Figure2)[2,72,73].Forexample,low‐
avidityCTLsremovetumorantigen‐MHCIcomplexesfromtargettumorcellswithout
killing,interferingwithtumorkillingbyhigh‐avidityCTLs[73].Likewise,CARandmon‐
oclonalantibodies(mAbs)alsomediatetumorantigenlossviatrogocytosis[2,72](seeSec‐
tion3.3).
Cells2021,10,11556of16
3.3.CAR‐MediatedTrogocytosis
CARscombineantigen‐bindingdomains,mostcommonly,asingle‐chainvariable
fragment(scFv)derivedfromthevariabledomainsofantibodieswiththesignalingdo‐
mainsoftheTCRζ chainandadditionalcostimulatorydomainsfromreceptorssuchas
CD28,OX40,and4‐1BB[74].AutologousTcellsengineeredtoexpressaCARspecificfor
CD19(CD19CARTcells)arehighlyeffectiveagainstseveraltypesofB‐cellmalignancies
andhaverecentlyreceivedFDAapprovalforuseinchildrenandyoungadultswithre‐
lapseofchemotherapyrefractoryacutelymphoblasticleukemia(ALL)andforadultswith
chemotherapy‐refractorynon‐Hodgkinlymphoma(NHL)[75].Despitethehighinitialre‐
sponseratewithCD19CARTcellsinALL,relapseoccurswithsometumorsbeinganti‐
gen‐negativeandothersantigen‐low[75–78].Arecentstudyusingamousemodelofleu‐
kemiademonstratedthatCD19istransferredtoCARTcellsviatrogocytosis,resultingin
removalofthetumorantigen[72].Suchalossoftumorantigenwasalsoobservedduring
cancertherapiesusingmAbssuchasrituximabandepratuzumab[2,79,80].Thisprocess
couldcausetumorescapevariants.Further,CD19‐acquiredCARTcellswereshownto
bekilledbytumor‐unexperiencedneighborCARTcells[72],aprocesscalledfratricide
(Figure2)[7].Therefore,theinhibitionoftrogocytosismayimprovetheefficacyofCAR
Ttherapy.Sincethespecificmolecularmechanismsoftrogocytosisremainunknown,as
aninitialstrategy,combinatorialtargetingcouldovercomethistrogocytosis‐basedside
effect.
4.Transplantation
4.1.AllospecificTCellPrimingbyCross‐Dressing
Tcell‐mediatedrecognitionofallogeneictransplantshasbeenconsideredtooccur
throughtwomainpathways(Figure3).InthedirectpathwayrecipientTcellsrecognize
intactMHCalloantigensondonorDCsresultinginacuterejection[81].Withtheindirect
pathwayallograftantigensareinternalizedandprocessedbyrecipientDCsandrecipient
Tcellssubsequentlyrecognizetheseantigens,whichpromoteschronicrejection[82,83].
Inadditiontothesepathways,thereisaccumulatingevidenceofathird,semidirectpath‐
way(cross‐dressingpathway)whereMHCalloantigensareacquiredbyrecipientDCs
(Figure3)[84–86]asdescribedbelow.
InbothhumanandmouseallogeneicDCcocultureassays,recipientDCsacquirean‐
tigen‐MHCcomplexesfromdonorDCs,andthesedonorMHC‐dressedrecipientDCs
primecognateTcellsinadonorMHC‐restrictedmanner,suggestingtheroleofcross‐
dressinginTcellalloreactionsinvitro[84,87].Inseveralmousemodelsofallograft(skin,
heart,orkidney)transplantation,recipientDCsinfiltrateallograftsandacquiredonor
MHC[88,89].Finally,theseDCsprimealloreactiveTcellsinadonorMHC‐restrictedman‐
ner,suggestingthatcross‐dressingindeedoccursinallografttransplantation(Figure3)
[88,89].However,thesestudiesdidnotaddresswhethercross‐dressedDCsareinvolved
inallograftrejectionandwhichDCsubsetcontributestothecross‐dressing[88].
Therelativecontributionofcross‐presentationandcross‐dressingtoCD8+Tcellac‐
tivationcanbeaddressedusingTAP−/−mice.TAPmoleculesaregenerallyrequiredfor
cross‐presentation,butnotforcross‐dressing(seeSection3.1).Ontheotherhand,thecon‐
tributionofDC1stoCD8+TcellactivationcanbeaddressedwithBatf3−/−mice,asthis
transcriptionfactorisrequiredforthedevelopmentofDC1s,butnotofDC2s[90].Re‐
cently,Lietal.usedtheseknockoutmiceandshowedthatwhenH‐2Kdskingraftswere
transplantedintoWTorBatf3−/−recipientH‐2Kbmice,Batf3−/−recipientmiceshowedde‐
layedrejection,suggestingthatrecipientDC1scontributetoallograftrejection[91].Alt‐
houghDC1shavecross‐presentingactivity,alloreactiveCD8+Tcellproliferationwasob‐
servedinTAP−/−miceaswellasinWTmice,suggestingthatDC1cross‐dressing,rather
thancross‐presentation,contributestoalloreactiveTcellactivation[91].However,itwas
notdirectlydemonstratedthatcross‐dressingisinvolvedinallograftrejection.Tothis
end,Hughesetal.usedB6(H‐2Kb/b)WTorH‐2K−/−recipientmicetransplantedwithH‐
Cells2021,10,11557of16
2K
b/d
kidneysexpressingthemembrane‐boundformofOVA;bothrecipientDCswere
foundtoacquireH‐2K
d
andH‐2K
b
‐SIINFEKL(OVA‐derivedpeptide)complexes.Two
daysaftertransplantation,thesemicewereadoptivelytransferredOT‐ICD8
+
Tcells.In
bothrecipients,acuterejectionwasequallyobserved,indicatingthatrecipientMHCIis
notrequiredforrejection.Toexcludethepossibilityofdirectpathways(Figure3),the
authorsshowedthatgraftsurvivalisprolongedwhenrecipientDCsweredepletedusing
theCD11c‐DTRsystem.Takentogether,thisstudyclearlydemonstratesthatcross‐
dressedDCsareinvolvedinallograftrejection[92].
Inthesemouseexperiments,recipientDCsacquireallo‐MHCfromthegraftnotonly
viatrogocytosis[87,93,94]butalsoviaextracellularvesicles[88,95],althoughitremains
unknownwhichisthedominantpathwayforcross‐dressingintransplantation.Italso
remainsunknownwhetherMHCdonorcellsingraftsareDCsorparenchymalcells.Fur‐
thermore,themostimportantquestionconcernswhethercross‐dressingisessentialfor
allograftrejectionbecausegeneticallyengineeredmiceinwhichcross‐dressingpathway
isspecificallyimpairedhavenotbeendevelopedsofar.
Figure3.Trogocytosisinallografttransplantation.AlloreactiveTcellactivationisinducedbythreepathways.Thefirstis
thedirectpathwaywhereintactMHCalloantigensondonorDCsarerecognizedbyrecipientTcells,promotingacute
rejection.ThesecondistheindirectpathwaywhereallograftantigensareinternalizedandprocessedbyrecipientDCs,on
whichdonorantigen‐recipientMHCcomplexesarerecognizedbyrecipientTcells,promotingchronicrejection.Thethird
pathwayisasemi‐directpathwayofso‐calledcross‐dressingwhererecipientDCsacquirepreformeddonorantigen‐MHC
complexesandarerecognizedbyrecipientTcells.
Cells2021,10,11558of16
4.2.InductionofAllospecificTCellTolerancebyCross‐Dressing
Incontrasttoskingrafts,allogeneiclivergraftsareacceptedinmicewithoutany
immunosuppressivetreatment[96].Inhumans,completeimmunosuppressionwith‐
drawalhasproventobefeasibleinapproximately20%oflivertransplantrecipients[97].
Theseobservationsledtothehypothesisofspontaneoustoleranceinlivertransplantation,
althoughtheunderlyingmechanismisnotwellunderstood.Onoetal.recentlyreported
that,inamousemodelofallogeneiclivertransplantation,recipientDCsinfiltrateinto
livergrafts,andacquiredonorMHC.Thesecross‐dressedDCsexpresshighlevelsofPD‐
L1,whichinvitrodidnotprimealloreactiveCD8+Tcells,butratherinducedtolerance
[98].Takentogether,theseresultssuggestthatcross‐dressingplaysaroleintolerancein‐
ductionalthoughwhetherthedepletionofPD‐L1highcross‐dressedDCscausesbreakdown
oftolerancehasnotbeenaddressed.
4.3.InductionofAllospecificTCellTolerancebyDouble‐NegativeT(DNT)CellTrogocytosis
TCRαβ+CD3+CD4‐CD8‐Tcells,socalleddouble‐negativeT(DNT)cells,comprisea
smallsubsetofmatureperipheralTcells,andthenumberofDNTcellsareexpandedin
variousinflammatoryconditions[99].Indeed,DNTcellshavebeenreportedtobein‐
volvedinseveralautoimmunediseasessuchassystemiclupuserythematosus(SLE),
Sjogren’ssyndrome,andpsoriasis,althoughthepreciseoriginandfunctionofDNTcells
isstillunderdebate[99].Incontrasttosuchpro‐inflammatoryactivity,areportedregula‐
toryfunctionofDNTcellsistheenhancementofallograftsurvival[100–102],inwhich
trogocytosisisinvolved[100,103].Forinstance,inamousemodelofskinallografttrans‐
plantation,recipientDNTcellsacquiredonorMHCIandinteractwithalloreactiveCD8+
Tcells.Duringthesecell‐cellinteractions,DNTcellslyseCD8+TcellsthroughtheFas/FasL
pathway,whichpreventsallograftrejection[100,103].Inaddition,ithasbeenrecentlyre‐
portedthatDNTcelltrogocytosissuppressesCD4+Tcellactivationinamousemodelof
allergy[104](seeSection6).
5.Infection
Cross‐dressing(seeSection3.1)alsocontributestoantiviralTcellresponses,which
hasbeenclearlydemonstratedbyWakimandBevanusingmousemodelsofviralinfec‐
tion[62].Inthisstudy,theauthorsutilizedirradiated(H‐2KdxH‐2Kb)F1micereconsti‐
tutedwithH‐2KdCD11c‐DTRbonemarrowcells,inwhichDCshaveonlyH‐2Kdandare
removablebyDTtreatment[62].FollowingadoptivetransferofOT‐ICD8+Tcellsand
infectionwithvesicularstomatitisvirusexpressingOVA,DCsacquiredtheOVApeptide‐
H‐2Kbcomplexfromthevirallyinfectedcells.Thesecross‐dressedDCswereessentialfor
memory,butnotnaïveOT‐ICD8+Tcellactivation,invivo[62].Smythetal.usedamouse
modelofOVA‐expressingadenoviralinfectiontoshowthatcross‐dressingactivatesnot
onlymemory,butalsonaïveOT‐ICD8+Tcells[63].BothstudiesdemonstratedthatDC2s
havemorepotentcross‐dressingactivitythanDC1sforantiviralimmunity,althoughthey
didnotuseBatf3−/−mice[62,63].Thediscrepancyregardingcross‐dressingofnaïveTcells
maybeascribedtodifferentamountsofMHCIandcostimulatorymoleculesoncross‐
dressedDCs.Inotherwords,naiveTcellscanbeprimedbyDCswithacquiredmembrane
fragmentsharboringlargeramountsofMHCIandcostimulatorymoleculesofvirallyin‐
fectedDCs,whereasmemoryTcellscanbeactivatedbyDCsdressedwithmembrane
fragmentsofvirallyinfectedparenchymalcells.
InadditiontocDCs,pDCsplayanimportantroleinimmuneresponsesbyproducing
largeamountofIFN‐Iduringantiviralimmunity(seeSection3.1)[41,43].Althoughitis
stillunderdebatewhetherpDCshaveantigenprocessingmachinery,pDCshavebeen
reportedtohavecross‐dressingactivity[64].ItwasalsorecentlyreportedthatpDCsgive
MHCItoDC1s,whichcontributestotheircross‐dressing[60].Sincethesestudiesmeas‐
uredonlyCD8+Tcellactivation,itremainsunknownwhetherdirectorindirectcross‐
dressingbypDCsindeedcontributestoantiviralimmunity.
Cells2021,10,11559of16
6.Th2Diseases
WhennaiveCD4+TCRsrecognizeantigen‐MHCIIcomplexesonAPCs,theseCD4+T
cellsexpandanddifferentiateintofunctionallydistincteffectorhelperT(Th)cellsubsets,
suchasTh1,Th2,andTh17cells[105].AmongtheseThsubsets,Th2cellsproduceIL‐4,
IL‐5,andIL‐13,whichplayacentralroleinhumoralimmunityandhostdefenseagainst
parasiteinfection,butalsohaveadetrimentalroleinallergicdiseasessuchasasthmaand
atopicdermatitis[105].TherearenumerousstudiesshowingthatnaïveCD4+Tcellsas
wellasCD8+Tcellsacquireantigen‐MHCcomplexesfromDCsduringthesecell‐cellin‐
teractions[68,69,94,106–110].UponinteractionwithDCs,CD4+Tcellsacquirenotonly
MHCII,butalsocostimulatorymoleculesandadhesionmoleculesthatarerecruitedonto
theimmunologicalsynapseformedatthecell‐cellcontactarea.Therefore,theseMHCII‐
acquiredCD4+TcellsareconsideredtoactasAPCs[94,106–109,111,112].Inaddition,
MHCIIacquisitioninducesprolongedTCRsignalingevenafterdissociationfromAPCs,
whichimpactsCD4+Tcellactivation,survival,andcytokineproduction[70].
InadditiontoCD4+TcellsandDCs,variousimmunecellsacquireMHCIIandare
involvedinTh2responses.Forinstance,basophils,themajorproducerofIL‐4[113],ac‐
quireMHCIIandactasAPCsforTh2differentiation[114].Group2innatelymphoidcells
(ILC2s),whichalsoproducehighamountsofTh2cytokines[115],persesynthesizeMHCII
butalsoacquireMHCIIfromDCsandactasAPCsinanti‐parasiticimmunity[116].
DNTcells(seeSection4.3)arealsoinvolvedinallergicasthma.Forinstance,ina
mousemodelofOVA‐inducedallergicasthma,adoptivetransferofDNTcellsameliorates
lunginflammation,mucusproduction,andOVA‐specificIgG/IgEproduction[104].In
thismousestudy,DNTcellsacquiredMHCIImoleculesfromDCsviaLag3/CD223,aCD4
homologue[117]thatbindstoMHCII.However,itremainsunknownhowthistrogocy‐
tosisisinvolvedinsuppressionofallergicinflammation.LikeTregulatorycells(Tregs)
[118](seeSection7),DNTcellsmayimpairtheantigen‐presentingactivityofDCsbystrip‐
pingoffMHCIIfromtheirsurface.Alternatively,MHCII‐acquiredDNTcellsactasregu‐
latoryAPCs,suchasMHCII‐acquiredNKcells[119]orlymphnodestromacells[120],
whichdonotexpresscostimulatorymoleculesandthusinduceCD4+Tcelltolerance[3].
7.TregTrogocytosis
TregssuppressconventionalTcellactivationviamultiplemechanisms[121,122].For
instance,TregsabsorbIL‐2andproduceimmunosuppressivecytokinessuchasIL‐10and
TGF‐β toinhibitTcellproliferationandfunction[121,122].Inadditiontothesedirectef‐
fectsonTcells,TregsconstitutivelyexpressCTLA‐4todown‐regulatetheexpressionof
costimulatoryligandssuchasCD80andCD86onDCs[123].Thisextrinsicfunctionof
CTLA‐4onTregsisdifferentfromthatoneffectorTcells,inwhichCTLA‐4transmitsthe
intrinsicinhibitorysignal.Treg‐specificCTLA‐4deletionindicatesthatTregCTLA‐4is
crucialforimmunesuppression[123].Interestingly,trogocytosisisinvolvedinthispro‐
cess.Specifically,TregshavebeenreportedtouseCTLA‐4toacquireCD80andCD86
fromDCsviatrogocytosis(Figure4)[124,125].Arecentstudyalsoreportedthatinduced
Tregs(iTregs)havehightrogocytosisactivitytoremovetheantigen‐MHCIIcomplexfrom
DCs[118].ThisactivityofiTregsishigherthanthatofnaïveandeffectorTcells[118],
whichisprobablyduetotheTregsformhavingamorestableimmunologicalsynapse(IS)
thanconventionalTcellsbyexcludingproteinkinaseC‐θ(PKC‐θ)fromtheIS[126].PKC‐
θhasshowntodestabilizetheIS[127].Takentogether,trogocytosismaybeinvolvedin
inductionofantigen‐specifictolerancebyiTregs(Figure4).
Cells2021,10,115510of16
Figure4.TrogocytosisinTreg‐mediatedimmunesuppression.TregcellsstripoffMHCIIandcostimula‐
torymoleculesfromDCsandasaresulttheseDCshaveanimpairedantigen‐presentingactivity.
8.ApplicationofTrogocytosis
Asdescribedabove,Tcellsmediatevariousdiseasessuchascancer,autoimmunity,
allergy,andinfectiousdiseases.However,inmanycases,pathogenicTcellsandtheirTCR
antigensremaintobeidentified,whichhampersunderstandingofpathogenesisandde‐
velopmentoftherapeuticapproaches.Toovercomethisproblem,severalapproachesfor
identificationofTCRantigenshavebeendeveloped[128–130].Inthiscontext,trogocytosis
mayalsobeappliedforclinicaldiagnosis.Specifically,severalstudieshaveutilizedthe
abilityofCD8
+
Tcellstoacquireantigenpeptide‐MHCIcomplexesinordertodetectan‐
tigen‐specificTcellsinperipheralbloodmononuclearcells(PBMCs)frompatientsin‐
fectedwithhumanT‐celllymphotropicvirustypeI(HTLV‐1)orlymphocyticchoriomen‐
ingitisvirus(LCMV).Tomaruetal.firstsuccessfullyidentifiedTcellpopulationsthat
specificallyrecognizetheHTLV‐ITax(11–19)peptidepresentedonHLA‐A*201[131].In
thisstudy,theauthorsestablishedHmy2.CIRcells,anHLA‐AandHLA‐Blocus‐defective
immortalizedBcellline,transducedwithHLA‐A*201fusedwithGFP.Whenthesecells
werecoculturedwithpatientPBMCs,HTLV‐I‐specificTcellsacquiredthepeptide‐HLA‐
GFPcomplexandbecameGFP‐positive[131].Thisisusefulfordetectionofantigen‐spe‐
cificTcellsfrombulkPBMCs;however,thisapproachislimitedbycelltype,colorspec‐
trumofGFPandrelatedproteins,andrestrictionofeachconstructtoasingleMHC.To
overcometheselimitations,BeadlingandSlifkadevelopedasimpleandversatilemethod
todetectpathogen‐specificTcellscalledT‐cellrecognitionofAPCsbyproteintransfer
(TRAP)assay[132].Specifically,theauthorsbiotinylatedthesurfaceofAPCs,followed
bylabelingwithstreptavidin‐fluorochrome.WhencoculturedwithLCMV‐infectedAPCs
labeledwithfluorochrome,virus‐specificTcellsacquiredAPCmembranefragmentsand
becamefluorochrome‐positive.Likewise,Daubeufetal.establishedamethodtodetect
antigen‐specificCD8
+
TcellsbyusingDil‐labeledAPCs[66].Importantly,thissimple
methodisnotlimitedbytypeofAPCandMHC[132].
InthecocultureofTcellsandAPCs,Tcellsinitiallyacquiretheantigenpeptide‐MHC
complexfromAPCsandsubsequentTCRsignalingstimulatesthesecretionofextracellu‐
larvesicles,whichareacquiredbyAPCs[26].Asaconsequence,thecell‐cellcontact‐de‐
pendentintercellulartransferofmembranefragments/vesiclesisviewedasbidirectional
trogocytosis(seeSection2).ByfocusingonAPCsthatacquireTcellmembranefragments
containingTCR,Lietal.haverecentlydevelopedthemethodtoidentifyTCRligand[6].
TheauthorsfirstgeneratedtheHLA‐A2‐restrictedsingle‐chaintrimercDNAlibrarycon‐
tainingmelanomaneoepitopesandthentransducedK562cells.WhencognateTCRrec‐
ognizesantigenpeptides,K562cellsacquiretheTCR,whichishighlydetectablebyFACS.
Aftersort‐purification,readingofthelibrary‐derivedantigensequenceenabledidentifi‐
cationofneo‐tumorantigens[6].
Cells2021,10,115511of16
9.Conclusions
Trogocytosishasbeenfrequentlyobservedduringimmunecellinteractionsandap‐
pearstobeinvolvedinvariousdiseases.Nevertheless,themolecularmechanismsunder‐
lyingtrogocytosisarestillpoorlyunderstood.Forinstance,cross‐dressingisinvolvedin
CD8+Tcellactivationincancer,viralinfection,andtransplantation;however,itremains
unknownhowDCsacquireMHCIfromdonorcellssuchasotherDCs,tumorcells,or
virallyinfectedcells.Moreover,howthedonorcell‐derivedMHCImoleculesareex‐
pressedontherecipientDCshasnotbeencarefullyaddressed.Asadetrimentaleffectof
trogocytosisduringtheCTLeffectorphase,theTCRaswellasCARstripofftargetanti‐
gensfromtumorcells,resultinginthegenerationofescapevariants.Thus,theinhibition
ofreceptor‐mediatedtrogocytosismayimprovetheefficacyofsomecancertherapies;
however,itiscurrentlyimpossibletoinhibittrogocytosiswithoutimpairmentofreceptor
functions.Itisalsounknownhowdonorcellsgivetheirmembranefragmentstorecipient
cells.Understandingofthemolecularmechanismsunderlyingtheseprocesseswillenable
thespecificperturbationoftrogocytosispathways,resultinginthedevelopmentofnew
therapeuticstrategiesfortreatmentofimmunediseases.
AuthorContributions:M.N.wrotethemanuscript.A.H.,S.T.,andS.‐I.Y.editedthemanuscript.All
authorshavereadandagreedtothepublishedversionofthemanuscript.
Funding:WorkintheNakayamalaboratoryissupportedbyJapanScienceandTechnologyAgency
(JST)PRESTO[JPMJPR17H9],JapanSocietyforthePromotionofScience(JSPS)[19H03880],and
UeharaMemorialFoundation.s
DataAvailabilityStatement:Notapplicable.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
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