CellsandTissuesoftheImmuneResponse
DrAllisonImrie
MICR2209
Synopsis:Inthislecturewewilldiscussthecellsand@ssuesoftheimmunesystemandtherolestheyplayininnateandadap@veimmuneresponses
Outcomes:Youshouldbeabletodescribethemajorcelltypesoftheimmunesystemandtheirlineage,andtheirbasicrolesininnateandadap@veimmunity
Allthecellularcomponentsoftheimmunesystemderivefrompluripotenthematopoie5cstemcellsin
foetalliverandbonemarrow
• Pluripotentstemcellsgiverisetocellswithprogressivelymorelimitedpoten@al
• Firstdivision:myeloid/erythroidvslymphoidpoten@al
• Myeloidprogenitorgivesrisetoallnonlymphoidcells:monocytes(whichgiverisetodendri@ccellsandmacrophages)andgranulocytes(neutrophils,eosinophils,basophils)
• LymphocyteprogenitorgivesrisetoNKcells,Tcells,andBcells,andcertaindendri@ccells
Colony-s@mula@ngfactors(CSFs)andinterleukinsaffectdifferen@a@onandmatura@on
Lymphocytes
• Lymphocytesaremostlysmallandinac@vecells
• Smallres@ngBandTlymphocyteshavenotyetencounteredan@gen;lookiden@cal
• S@mula@onbyan@geninducesthelymphocytetobecomeanac@velymphoblast• Lymphoblastsproliferateanddifferen@atetoeffectorTandBlymphocytes
ClassesoflymphocytesAn5genrecogni5on Effectorfunc5on
Bcells
• Blymphocytesrecognizesolubleorcellsurfacean@gensanddifferen@ateintoan@body-producingcells,calledplasmacells• An@bodieseliminatean@gensby:
! Neutralizingtheabilityofmicrobestoinfecttargetcells! Labelingmicrobes(opsonizing)forphagocytosis! Ac@va@ngthecomplementpathway
ClassesoflymphocytesAn5genrecogni5on Effectorfunc5on
HelperTcells(CD4+)
• HelperTlymphocytesrecognizean@genonthesurfaceofan@gen-presen@ngcells,andsecretecytokineswhichs@mulatedifferentmechanismsofimmunityandinflamma@on:
! Ac@va@onofmacrophages,toenhancephagocytosis! Ac@va@onofBcellstoproducean@bodies! Ac@va@onofCD8+killerTcells
ClassesoflymphocytesAn5genrecogni5on Effectorfunc5on
CytotoxicTlymphocytes(CD8+)
• CytotoxicTlymphocytes(CTL)recognizean@genoninfectedcellsandkillthesecells.Thisisamajormechanismforcontrollingintracellularpathogens• Naturalkiller(NK)cellsrecognizeinfectedcells,usingdifferentmechanismsthanCTL,andkillthem
NaturalKillercells
Macrophagesarephagocyteswhicheradicatemicrobesandalsoactasan5genpresen5ngcells
MHCClassIImoleculepresentspep@deoncellsurfaceforsurveillancebyCD4+Tcells
Macrophagesprocessingestedan@gentopep@des
1oand2oLymphoidTissue
PrimarylymphoidorgansareorgansinwhichBandTcellsmature.Whilstmaturingtheylearnhowtodifferen@atebetweenhostcells(towhichtheydonotrespond)andforeignpathogens.Secondarylymphoidorgansareinvolvedinthepresenta@onofforeignan@genstoTandBcellstoac@vatetheadap@veimmunesystem.
Lympha5cSystemThelympha@csystemisadrainageandfiltra@onsystemthatenablesinters@@alfluidandplasmaproteinstoflowbackintoblood.Itisalsoasystemforlymphocytecircula@onandan@[email protected]@lageandepidermis.Systemstartsaslymphcapillaries(closedend)[email protected]@onduetopressurefrommuscleac@onandonewayvalves.Lymphfromallpartsofbodyentersbloodstreamviasubclavianveinsandthoracicduct.Lymphisaclearliquidcontainingproteinsandlymphocytesandan@genpresen@ngcells(APC)
BoneMarrow• BothTandBlymphocytesoriginateinbonemarrow.• Bcellsdevelopfromlymphoidstemcellsinfoetalliver
hematopoie@c@ssueat8-9weeks• Produc@onmovestobonemarrowwhereitcon@nuesthroughadult
life• BonemarrowissiteofBcelldevelopmentinmammals.• PrecursorTcellsmigratetothymusformatura@on• Followingan@genics@mula@oninlymphnodegerminalcentres,
matureBcellscandevelopintomemorycellsoran@genformingcells(AFC)
Summary:Bcellsdevelopinbonemarrowandmigratetoperipherallymphoidorgans,wheretheycanbeac5vatedby
an5gen
Thymus
• Mul@potentTcellprogenitorsformedinfoetalliverandbonemarrowenterthymusviahighendothelialvenules(HEV)andmigratetowardscortex
• Tcellprogenitorsundergoprolifera@onanddifferen@a@onincortex
• MatureTcellsleavethymusviaHEVandentercircula@on
Arrows:transloca@nglymphocytesArrowheads:highendothelialcellsofHEV
Arrowheads:highendothelialcellsofHEV;transloca@nglymphoytesareshown
Themammalianthymusinvoluteswithage
• Inhumansatrophybeginsatpubertyandcon@nuesthroughoutlife
• Involu@onbeginswithinthecortex,whichmaydisappearcompletely
• Cor@calatrophyisverysensi@vetocor@costeroids;promotedbypregnancyandstress
• LikelythatTcellgenera@onwithinthymusdoescon@nueintoadultlife,atamuchlowerrate
Involu@onofthethymuswithreplacementbyadipose@ssue
Summary:Tcellsdevelopinbonemarrowandmatureinthymus.Theymigratetoperipherallymphoidorgans,wheretheycanbeac5vatedbyan5gen�
Onleavingbonemarrowandthymus,lymphocytesmigratetosecondarylymphoidorgansand@ssuesinspleen,lymphnodes,andmucosa-associatedlymphoid@ssue(MALT),wheretheyencounteran@genpresentedbyAPC
Naïvelymphocytes(thosewhichhaveneverencounteredan@gen)encountertheirspecifican@gen,andareac@vated,intheperipherallymphoidorgans
MucosalAssociatedLympha5cTissueSamplesan@genfromepithelialsurfaces
MALTshowninblue
Lymphoid@ssuesarefoundassingleoraggregatednodules
MALTincludesgut-associatedlymphoid@ssue(GALT)andbronchus-associatedlymphoid@ssue(BALT)
Peyer’sPatchesarelymphoidnodulesfoundthroughoutsmallintes5ne(ileum)
PathogensinthegutaresampledinPPbyMcells
Primedlymphocytesmigratetomesentericlymphnodesthentoeffectorsites
Mcellstranscytosean@gentomucosallymphoid@ssueundertheepithelium
Lymphocytesencounter,andareac5vatedby,an5gensbroughttolymphnodes(vialympha5cs)byan5genpresen5ngcells
Naïvelymphocytes(whichhavenotyetencounteredan5gen)entertheLNviathecircula5on
Lymphnodes
TcellsandBcellsareseparatedintoseparateanatomicalcompartments:BcellsareconcentratedinfolliclesintheLNcortex.Ac@vated,prolifera@ngBcellsarelocatedinthegerminalcentres.
Tcellsarelocatedintheparacortex.Whenlymphocytesareac@vatedbymicrobial
pathogens,theymigratetowardseachotherandmeetattheedgeofthefollicles,whereThelpercellsinteractwithandhelpBcellstodifferen@ateintoan@body-producingcells.
Ac@vatedTcellsandBcellsleavetheLNthroughefferentlympha@cvessels,enterthecircula@on,andmigratetodistantsitesofinfec@on.
LymphNodeandAPCLNcontain3APCtypes,eachdealingwithdifferentkindsofan@gen:• DCpickupan@genatperipheryand
migratetoTcellrichzonesinLN• MacrophagesarepresentthroughoutLN
andmonitorlymphentryandexit–theyphagocytosepathogensandpresenttoTcells
• Bcellsmonitorsolublean@genfrompathogensandpresentinGC
Dendri@ccellsundergochangesinappearanceduringtheprocessofmatura@onandmigra@onfromperipheral@ssuestolymphoid@ssuesthroughthelympha@ccircula@on
Dendri@ccellssamplean@genfromthroughoutthebody,andmigratetolymphnodes(viathedraininglympha@cs)topresentan@gentoTcells
Dendri5ccellscanprocessan5genfromawidearrayofpathogens
Lymphadenopathy
Swollenlymphnodesinapa@entwithonchocerciasis
• Generalizedinfec@ous
lymphadenopathy,causedmostlybyviralinfec@on,resultsinnodalhyperplasiawithoutnecrosis,andresolvesspontaneouslyastheillnessresolves
• MicrobescanreachLNvialymphorblood.Localcytokinereleaseresultsinneutrophilrecruitmentandvascularengorgement.Thenodeeventuallyheals.MacrophagesinLNalsophaocytosean@gen
Spleen• Thespleenhasnodirectcontactwithlympha@cs:filtersblood• Whitepulpcontainssheathoflymphocytes,mostlyTcells(theperiarteriolarlymphoidsheath,orPALS)aroundanarteriole.Lymphoidfollicles,andgerminalcentres,containBcells• An@genspresentinblood-bornepathogensarefilteredfromthebloodbymacrophagesandDCwithinthemarginalzone.TheseDCthenmovetoPALSandpresentan@gentoTcells• RedpulpissiteofRBCdisposal