The
labyrinth
unfolds:
architectural
rearrangements
of
the
endolysosomal
system
in
antigen-presenting
cells
Priscillia
Perrin,
Marlieke
LM
Jongsma,
Jacques
Neefjes
and
Ilana
Berlin
Antigen-presentingcells(APCs)captureandpresent
pathogenstoTcells,thusarousingadaptiveimmune
responsesgearedattheeliminationoftheseinvaders.InAPCs,
pathogensacquiredfromtheextracellularspaceintersectwith
MHCclassII(MHC-II)moleculesintheendolysosomalsystem,
whereprocessingandloadingofantigenicpeptidesoccur.The
resultingcomplexescanthenbedirectedtothecellsurfacefor
recognitionbyTcells.Toachievethis,theendosomalpathway
ofAPCsmustundergodramaticrearrangementsupon
pathogenencounter.Inthisreviewwediscussrecentstridesin
ourunderstandingofhowAPCsmodulatetheorganizationand
functionoftheirendolysosomestobestsuitdifferentstagesof
antigenacquisition,processingandpresentationcascade.
Address
OncodeInstitute,DepartmentofCellandChemicalBiology,Leiden
UniversityMedicalCenter,Einthovenweg20,2333ZC,Leiden,The
Netherlands
Correspondingauthor:Berlin,Ilana(I.Berlin@lumc.nl)
CurrentOpinioninImmunology2019,58:1–8
ThisreviewcomesfromathemedissueonAntigenprocessing
EditedbyJoseVilladangosandJustinMintern
https://doi.org/10.1016/j.coi.2018.12.004
0952-7915/ã2018ElsevierLtd.Allrightsreserved.
Introduction
The endolysosomal system functions as atrading plat-form through which the cell and its environment exchange information and goods in order to maintain homeostasisandcommunicateimpendingpredicaments. To enablereceptionandutilization ofawidevarietyof materialsandsignals,thissystemcomprisesmany differ-ent flavorsof vesicularmembrane carriers, whose inter-actionswithoneanotherdeterminedownstreamcellular outcomes.Followinginternalizationfromthe extracellu-lar space, endosomes undergo progressive maturation, characterizedbyacidificationandsortingofubiquitinated cargoes intointraluminal vesicles (ILVs).The resulting multivesicularbodies(MVBs)cansubsequentlyfusewith lysosomes to deliver the contents of their ILVs for
degradation[1],whilematerialsnotintendedfor degra-dation recycle from the limiting endosomal membrane back to the cell surface. Cytoplasmic cargoes encapsu-latedwithinautophagosomesalsofeedintothisendocytic tract for access to the proteolytic compartment, thus allowingcross-talkbetweenintracellularandextracellular domains[2].Thisdiversesystemofvesiclesmustworkin concerttofulfillitsrolesasthecell’ssensoryplatformand digestive organelle. To ensure controlled uptake and progression of cargoes through the system, cells have evolvedstrategiestoorganizeandmanipulatetheir endo-lysosomalrepertoireinspaceandtime.Inthisreview,we discussthenatureof thesestrategiesandtheir relation-ship(s) to endocytic function at the host–pathogen interface.
antigen-presentingcells can contributeto the develop-mentofauto-immunity.
‘Class
II’
goes
to
the
MIIC
Following their biosynthesis and association with the invariantchainchaperone(Ii)intheendoplasmic reticu-lum (ER), MHC-II dimers traffic via the trans-Golgi network to theso-called MHC-IIcompartment (MIIC) known to host antigen processing and peptide loading (Figure1)[6].AlthoughMIICscanvaryinstructureand
maturationstate,theygenerallycompriselateendosomes or lysosomes characterized byintraluminal membranes, acidic pH, and mild proteolytic activity—all attributes thatfavorantigenprocessingandpreservationofresulting epitope integrity [4]. When antigens acquired through endocytosis,phagocytosis,macropinocytosis(exogenous), orautophagy(endogenous)entertheendocytictract,they aredirectedtotheMIICfordegradation[7,8].Antigenic peptides produced during this process can then be directlyloadedontoMHC-IIresidinginthesame com-partment.Tofacilitatepeptideloading, MHC-II-associ-ated Ii must undergo proteolysis [9], leaving only the contiguous internal segment of Ii (CLIP) within the MHC-II peptide-binding groove [10]. The endosomal chaperone HLA-DM then mediates removal of CLIP, creatingan opportunityfor antigen-derivedpeptides to bind[11].
Under steady state conditions, most MHC-II dimers, alongwithHLA-DM,aresequesteredontoILVsofthe MIIC[12].IntraluminalsortingofMHC-II, aswellas vesicle budding and scission, is orchestrated by the endosomal sorting complexes required for transport (ESCRT)[13]andlikelyrequiresMHC-II ubiquitina-tionbyligasesofthemembrane-associated RING-CH (MARCH) family [14], although the impact of this modification onantigen presentationremains debated [15].BeforeincorporationintoILVs,ubiquitinmaybe removedandrecycledfromsortedMHC-IIuponaction ofdeubiquitinatingenzymes[16].Eventually,MHC-II reaches intraluminal membranes, whose composition greatly differs from that of the limiting membrane. ILVsarehighlyenrichedincholesterolandtetraspanin proteins(CD63,CD81andothers)[17],and sequestra-tionofMHC-IIinthelumenoftheMIICmay, there-fore, have functional consequences. Indeed, FRET studies have indicated that MHC-II and HLA-DM interactonILVmembranes,ratherthanonthelimiting membrane of the MIIC [18], implying that MHC-II peptideloadingmaycomprehensivelyoccuroninternal vesicles.Whileintraluminaltetraspaninnetworkshave been suggested to stabilize DM-MHC-II interactions andfacilitatepeptideloadingonILVs[19],cholesterol likely plays asubstantial role inMHC-II intracellular traffic[20].
InimmatureAPCs,MHC-II-positiveILVsareeventually degradedin lysosomesorreleased fromthecellas exo-somes[21].Followingencounterwithapathogen, how-ever,MIICstransitionfromILV-richantigen-producing and loading factories to tubular organelles, poised for transport of mature MHC-II complexes to the plasma membraneforrecognitionbyTcellreceptors[22].How theMIICis organizedand remodeledto bestservethe hostduringdifferentstagesoftheinfectionprocess—and howthesesameattributescanbeutilizedbythepathogen togainadvantageoverthehost—isdiscussed below.
Figure1 MHCII ER GOLGI H+ H+ H+ DM H+ H+ H+ H DM Endosome Phagosome Auto phagosome H+ H+ MIIC/endolysosome Myo1e Arl14 Actin Ub RNF26 Ub Arl8b PLEKHM1 Rab7HOPS
CLIP
Ii
Protease Ag
Current Opinion in Immunology
SchematicoverviewofMHC-IIantigenpresentationinAPCsbefore
maturation.
InimmatureAPCs,MHC-IIincomplexwiththeinvariantchainIiexits
thebiosynthetictractviatheTGNandistargetedtotheendosomal
pathwayeitherdirectlyorviatheplasmamembrane.OnceMHC-II/Ii
complexreachestheacidicandproteolyticMHC-IIcompartment
(MIIC),muchofIiistrimmedawayandMHC-II/CLIPawaitsantigens.
AftersortingintoILVs,MHC-IIinteractswithHLA-DMforpeptide
loading.AsAPCssampletheirenvironmentandcollectantigens(Ag)
throughvariouspathways(exogenous:endocytosis,phagocytosis;
endogenous:autophagy),theseareroutedtotheMIICforprocessing,
loading,andpresentation.Thisrequiresretrogradevesicletransport
towardthemicrotubuleminus-endwhereantigenprocessing
compartmentsareretainedbyER-associatedRNF26.Fusionwith
theseendolysosomesisthenorchestratedbythesmallGTPasesRab7
andArl8binconjunctionwiththeireffectorsRILP,PLEKHM1and
HOPS.Additionally,Arl14/Myo1ecomplexinhibitsexportofp-MHC-II
Before
the
invasion—organization
of
the
endolysosomal
system
in
immature
APCs
InnumerousAPCs,includingmacrophagesandimmature monocyte-derived DCs(moDC), the endolysosomal sys-temfeaturesabilateralarchitecture,comprisedofarather immobileperinuclear(PN)vesiclecluster,or‘cloud’,anda highly dynamic peripheral pool of endosomes and lyso-somes[23].Thefateofindividualvesiclesineitherregion of the cell relies on small GTPases, which determine directionalityoftransportbetweenthePNcloudandthe peripheryandorchestratematurationandcargoexchange [24].Throughinteractions withvariouseffectorproteins, GTPasesoftheRab,Arf,andArlfamiliescouplevesiclesto microtubulemotors fordirectionaltransportandmediate recruitmentofremodelingfactorsrequiredformembrane fusionandfission.AtleasttwoGTPases,Rab7andArl8b, associated with late endosomes and lysosomes, oversee trafficflowalongtheantigenprocessingandpresentation cascade (Figure1) [25,26]. Rab7, in complex withitseffector Rab-interactinglysosomalprotein(RILP)andthe microtu-bule-baseddyneinmotor,transportsmaturingendosomes includingthosecontainingantigenstowardthePNcloud, where degradation occurs. Rab7 then collaborates with Arl8b through a shared effector Pleckstrin homology domaincontainingproteinfamilymember1(PLEKHM1) and its associated homotypic fusion and protein sorting (HOPS) complex to promote fusion betweenlate endo-somesandlysosomes[27],therebyensuringcargo degra-dationandacquisitionofantigenicpeptidesbyMHC-II. Spatiotemporalregulationofendolysosomalorganization and behavior is not only autonomously determined, as described above, but is also influenced by other orga-nelles,mostnotablytheendoplasmicreticulum(ER).For instance, endosomes entering the PN cloud can be anchoredandretainedthroughinteractionswiththe peri-nuclear ER-associatedubiquitin ligase Ring finger pro-tein26(RNF26),andthisERdockingfacilitatesaccessof incomingvesiclestolatecompartments(Figure1)[23]. Furthermore,fissionofendosomesisalsocuratedbythe ER [28,29]. As these processes are crucial for faithful sorting and timelydeliveryof internalizedmaterialsfor proteolysis, it stands to reason that their underlying mechanisms would also influence efficiency of antigen processingandpeptideloading,althoughformal investi-gation thereofremainsto beperformed(Table1).
The
fight
is
on—architectural
changes
in
the
endolysosomal
system
upon
APC
maturation
Intheearlysteps ofpathogenicinvasion,APCsbecome activateduponbindingofinnateimmunereceptors,such asToll-likereceptors(TLRs),topathogenicligandsand integrationofinflammatorymediatorsproducedbyother cell types. As a result, APCs embark on a cell-wide maturation program, which transiently increases MHC-IIbiosynthesis,inhibitsantigenacquisitionthrough non-specific phagocytosis and macropinocytosis [4], and
demands dramatic reorganizationof the MIIC architec-ture[4].Followingactivation,MIICstransitionfromtrue MVBstotubularendolysosomesdevoidofinternal mem-branes in order to allow efficienttrafficking of peptide-loadedMHC-II(p-MHC-II)totheplasmamembranefor presentation [30,31]. How MHC-II is transferred from ILVstothelimitingmembraneoftheMIICisunclear.It hasbeenspeculatedthat,followingAPCactivation, pre-existing multi-vesicular MIICs would fuse with lyso-somes, leading to degradation of pre-loaded MHC-II residingoninternalmembranes.Meanwhile,newly syn-thesized MHC-II would traffic to these late compart-mentsbutavoidbeingsortedintoILVsduetosuppressed ubiquitination [32], remaining instead on the limiting membrane for peptide loadingand transport. However, this supposition is challenged by the observation that most p-MHC-IIcomplexes are deliveredto the plasma membranebeforeMHC-IIubiquitinationandsortingare downregulated[30,33].Sohowthendoespeptide-loaded MHC-IIarriveatthelimitingMIICmembranetoenter tubulesfortransport?Ithasbeenproposedthatinsteadof suffering degradation, ILVs harboring p-MHC-II fuse back withthe limitingmembrane of theMIIC through a process termed ‘retrofusion’ (Figure 2) [34–36]. The existence of such a path for ILVs carrying p-MHC-II complexes would explain a number of observations. Firstly,thenotionthatsurfacep-MHC-IIoriginatesfrom cholesterol-laden ILVs is notably consistent with the finding that MHC-II arrives at the plasma membrane in cholesterol-richmicroclusters[37].Moreimportantly, since APC stimulation occurs concurrently with the acquisition and processing of pathogenic antigens, the abundant luminalpool of p-MHC-II constituted before maturation likely encompasses a myriad of pathogen-specific epitopes,andits eliminationwouldbe counter-productive to antigen presentation. Retrofusion would thus offer a path for rescue of these epitopes from lysosomal degradation, allowing them to be presented. Intheend,thetwomodelsforMHC-IItransferprobably coexist, and p-MHC-II complexes from all possible sources contribute to antigen presentation in order to achieve optimalimmunestimulation.
Table1
Openissuesonendosomalmodulationinthecontextofantigen
presentation Issue
Endosomalmodulationsinautoimmunediseases
TheregulationofautophagyinTECs
Pathogen-mediatedalterationsoftheendocyticnetworkinAPCs
Themolecularmechanismofretrofusion
FunctionaldifferencesbetweenILVsandthelimitingmembraneofthe
MIIC
ER-mediatedcontrolofendosomalprocessesinprofessionalAPCs
Themolecularpathwayleadingtoendosomaltubulationand
Given its small physical scale and dynamic nature, the processofretrofusionhasnotyetbeendirectlyobserved (Table 1). However, viruses and toxins have been described to hijack this pathway, following endosomal entry,in order to reach thecytosol ofthe host celland achieve infection[38–40].Similarly, it hasbeen specu-latedthatretrofusionmayallowaccessofexosome encap-sulatedmaterialto thecytosol oftargetcells[41].
‘Ins’
and
‘outs’
of
MHC-II
transport
to
the
cell
surface
Once p-MHC-II complexes have reached the limiting membrane of the MIIC, they are sorted into tubules destinedfortransport tothecellperiphery.Subsequent fusion of p-MHC-II positive tubules with the plasma membrane implants these antigen epitopes for T cell recognition.Whileretrogradetransporttotheperinuclear regionisgovernedbydynein,asdescribedabove, anter-ogradetransport towardtheplasmamembranerelieson
kinesin-1motoractivity[42,43].Intriguingly,both anter-ogradeandretrogradetransportappeartobeessentialfor MHC-II delivery to the cell surface. In macrophages, lysosomaltubulationrequiresbothRab7andArl8b,and lipopolysaccharide(LPS)stimulationtriggersthisprocess inamammaliantargetofrapamycin(mTOR)-dependent manner[44,45].ItisthoughtthatArl8b-mediated kine-sin-1 activity drives lysosomal elongation into tubules, and together with the counter force provided by the Rab7-dyneincomplexresultsintubulefissionand liber-ationofp-MHC-IIcarriers(Figure2)[46].Recentwork revealsthatTLR-dependentengagementofthemTOR axisinducesmembrane accumulationofArl8b [45],but the precise molecular underpinnings thereof remain unexplored (Table 1). The multisubunit BLOC-one-related complex (BORC) known to stimulate Arl8b recruitment and influence positioning of lysosomes in the cell periphery is likely involved [47–49], but the existence of additional regulatory layers cannot be
Figure2 ER GOLGI MHC II cholesterol rich microdomains + Arl8b RILP Rab7 BORC TLR Signalling Retrofusion MHCII Arl14 Actin H+ H+ H+ DM H+ H+ -Kinesin-1 Dynein MIIC/endolysosome Ii Protease
Current Opinion in Immunology
SchematicoverviewofMHC-IIantigenpresentationinmaturingAPCs.
Uponrecognitionofpathogensbyreceptors,suchasTLRs,APCsundergoaprocessofmaturation,duringwhichglobalrearrangementsofthe
endolysosomalsystemtakeplace.IntheMIIC,retrofusionofILVsandrestrictionofintraluminalsortingmayallowp-MHC-IIcomplexestoreach
thelimitingmembraneoftheendolysosome.BORC-mediatedrecruitmentofArl8btotheMIICleadstoengagementofkinesin-1motorthatdrives
elongationofMHC-II-positivemembranesintotubulestowardthemicrotubuleplus-end.Concomitantly,Rab7-RILP-dyneintransportcomplex
providesanopposingforcenecessarytoinducemembranefission.OncetheresultingMHC-IIcarriersreachtheperiphery,theyfusewiththe
excluded.Rab7canalsomediateendolysosomaltransport tothecellperipheryviaitseffectorFYVEandcoiled-coil (CC)domain-containingprotein(FYCO1)[50].Whether thistraffickingrouteparticipatesindeliveryofp-MHC-II complexes to the plasma membrane of APCs is not known.
Collectively, diverse transport systems are needed to properly control traffic of MHC-II-containing vesicles to theplasmamembraneduring APCmaturation. Inter-estingly,althoughthesamemachineriesarealsopresent inimmatureAPCs,intheabsenceofappropriatetriggers, MIICsdonotmigratetothecellsurface,suggestingthe existenceof inhibitory mechanisms.Indeed,in a multi-dimensional depletion screenthe small GTPase Arl14/ Arf7 was identified as a negative regulator of MHC-II export in moDCs [51]. Association of Arl14 with Arf7 effector protein(ARF7EP)causesrecruitment ofmotor myosin1EforanchorageofMIICstotheactin cytoskele-ton(Figure1).Bycontrast,inactivationofthissystemin immature DCs sends MHC-II molecules to the cell surface, recapitulating a mature DC phenotype in the absenceof activation(Figure 2).
Oncetheexportofpeptide-loadedMHC-IIcomplexesis achieved,theirstableresidenceattheplasmamembrane is protectedtoensure longevityof antigen presentation [52].Ifendocytosed, owingtolackof ubiquitination, p-MHC-IIs recycle back to the cell surface, instead of following the degradation route [53]. Hence, MHC-II ubiquitination must be tightly controlled to best serve APC function throughout the immune response. For
example,ingerminalcenters,Bcellsareselectedbased on their ability to capture and present antigens to T helpercells.Inordertofavortheirselectionand prolifer-ation, thesecellsmodulateMARCH1-mediated ubiqui-tination of MHC-II dimers to promote presentation of theirmostrecentlyacquiredantigens[54].Timely tun-ingofMHC-IIturnover,therefore,contributestotherise of high-quality antibody responses. In contrast, when triggeredbypathogens,aberrantubiquitinationand sur-face depletionofmature MHC-IIdimerscanhave dra-maticconsequencesonTcellactivation.Forinstance,the gram-negative bacteria Salmonella enhances MARCH8-dependant ubiquitination of endocytosed p-MHC-IIs, thereby hamperingtheirrecyclingand dampening anti-gen presentation to T cells (Figure 3) [55]. Taken together,thesestudiesillustratethepowerofmodulating ubiquitinationstatusofMHC-IIandsuggestavenuesfor intervention through transient inhibition of the enzy-maticactivitiesinvolved.
Antigen
presentation
and
tolerance:
how
alterations
in
MHC-II
traffic
and
autophagy
set
off
autoimmunity
Because APCsplayapivotalrolein theriseofimmune defenses,tightcontrolovertheirfunctionisessentialfor immunetolerance.DeregulationofMIICdistributioncan leadtoexcessiveantigenpresentationandresultin auto-immune disorders. For instance, the C-type lectin CLEC16Awasidentifiedasafactorresponsibleforsuch deregulations in a genome-wide screen combined with multiplesclerosisdatasets[56].Increasedexpressionof CLEC16A causes abnormal MIIC biogenesis, which
Figure3 SteDD MARCH8 Ub Salmonella Degradation
Multiple Sclerosis
H+ H+ H+ RILP Rab7 DM CLEC16A HOPS
MIIC maturation --> self-Ag loading
Self-Ag Protease MHCII MIIC H+ H+ H+ H H+ H+ H+ H+ H MIIC Auto phagosome Self-Ag CTLA-4 PI3K/Akt/mTOR Foxp3+ Treg Ag AUTOIMMUNITY
(a)IMMUNE EVASION (b) (c)AUTOIMMUNITY PROTECTION
Current Opinion in Immunology
AlterationsintheMHC-IIendocyticpathwaycanpromoteimmuneevasionandleadtoautoimmunity.
(a)SalmonellabacteriaevadehostantigenpresentationbymanipulatingtheendocyticrouteofMHC-II.Salmonella’seffectorSteDpositively
regulatesMARCH8-mediatedubiquitinationofendocytosedp-MHC-IIcomplexes,preventingtheirrecyclingtothecellsurface.(b,c)Malfunctions
inMHC-IIand/orantigentraffickingpathwaycanresultinaberrantantigenpresentationandleadtoautoimmunity.(b)Inmultiplesclerosis,theC
typelectinCLEC16AenhancesmaturationofMHC-IIpositiveendosomes,likelythroughinteractingwithRILPandtheHOPScomplex.Altered
MIICbiogenesisallowsforloadingandpresentationofself-antigensandmaytriggeranautoimmuneresponse.(c)Theautophagypathway
deliversauto-antigenstotheMIICforloadingandpresentationbyMHC-II.Inordertopreventautoimmunity,regulatoryTcellsdisruptthe
couldaffectCD4Tcellactivationandresultin autoim-muneresponse(Figure3).SinceitassociatestoRILPand the HOPS complex, CLECL16A may affect transport and fusion of MHC-II-carrying endosomes with lyso-somesand thus alter MHC-IIpeptide loadingand pre-sentation of autoantigens. Hence, conservation of self-tolerance not only requires proper MHC-II trafficking, butalsodependsonthedeliveryofself-antigensto MHC-II carriers. This can be achieved by macroautophagy, when cytosolic substrates reach the endocytic network inautophagosomalmembranes.InDCs,fusionof autop-hagosomeswithMIICsleadstoprocessingandloadingof cytosolicself-antigens ontoMHC-II for presentation to effectorTcells.Interestingly,Foxp3+Tregcellsdisrupt autophagyin DCs (draining lymph nodes, splenic, and bone marrow-derived DCs) through CTLA-4 engage-mentandconsecutiveactivationofthePI3K/Akt/mTOR pathway (Figure 3) [57]. The resulting deficiency reduces CD4T cellauto-reactivity and lowersthe risk ofautoimmunity.
Incontrast, autophagyin thymicepithelial cells (TEC) drivespresentationofself-antigenstothymocytesandhas thus been implicated in T cell selection [58,59]. CLEC16Awasrecentlyfoundtoinfluencethymic selec-tionvia autophagy, and its depletioncould counterthe development of autoimmunity [60]. Precisely how CLEC16A regulates TEC autophagy is unknown, but itmayinvolvemodulationofmTORactivity[61],aswell asimplicateRILP andHOPS. Thelatteroptionis sub-stantiated by the finding that transport and fusion of autophagosomes with late endosomes and lysosomes are timed by several Rab7 effectors, including RILP, PLEKHM1 and the cholesterol sensor ORP1L [62]. Specifically,theseprocessesaresensitivetothepresence of cholesterol in endolysosomal membranes, as choles-terol depletion forces Rab7-bound ORP1L to mediate contacts with the ER. As a consequence, retrograde transport and maturation of autophagosomes are inhib-ited.Itis,therefore,plausible thatCLEC16A interven-tionatthisjuncturemayalterdecisivestepsinautophagy toinfluenceimmunetolerance.
Conclusions
and
perspectives
Theendosomalpathwaysofcellsentrustedwith respon-sibilitiesofantigenprocessingandpresentationaremore diverse and dynamic than originally anticipated. The architectureanddynamicsof theendolysosomalsystem in APCs are controlled by various factors, which ulti-mately determine healthy MHC-II responses. New insightsonthiscomplexnetworkofvesicularorganelles discussedinthisreviewexpandourperceptionof MHC-IIfunction,and itsnumerousforms ofmodulation, and edifyourunderstandingoftheMHC-IIcompartmentto illustratehowendosomalregulatorscontributeto scrupu-lousimmuneresponsesandtolerance.Decipheringhow theendolysosomalarchitectureismodifiedinthecourse
ofinfectionsandautoimmunediseases(Table1)willhelp definetherapeutictargetsandultimatelytodesign appro-priateclinical strategies.The firstexamples are now at hand.
Conflict
of
interest
statement
Nothingdeclared.
Acknowledgements
ThisworkwassupportedbyanERCAdvancedgrantandtheNWOGravity
grantawardedtoJN.
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