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@genpresenta@on.Systempresentthroughoutbodyexceptcar@lageandepidermis.Systemstartsaslymphcapillaries(closedend)lympha@cvesselslymphnodelymphductblood.Fluidflowsonlyinonedirec@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