Thecentralnervoussystem(CNS)isconsideredtobeanimmune-privilegedsiteowingtovariousspecificconditions.First,theexpressionofMHCmoleculesislimitedwithintheCNSparenchyma1.Second,theentryofadaptiveimmunecellsintotheCNSviatheblood–cerebrospinalfluid(CSF)barrier,theCSF–brainbarrierandtheblood–brainbarrierisrestricted2–5.Third(andperhapsmostimportantly),theantigenicrepresentationoftheCNSinperipherallymphnodesmaynotfaithfullyrecapitulatetheantigenicrepertoireoftheCNSowingtospecialfeaturesofthe‘lymphatic’drainageoftheCNS6,7.Asaresult,theadaptiveimmunesystemmightbeignor-antofnumerousantigensthatareexpressedintheCNSparenchyma.AsmanyautochthonouscellsoftheCNSarepost-mitoticandareintegratedintohighlyorganizedfunc-tionalcircuits,adaptiveimmuneresponsesintheCNSaredelicate,andinflammationintheCNSisafinetrade-offbetweencontrolofinfectiousagentsandimmune-mediateddamage.Nevertheless,steady-statepatrollingofdistinctpartsoftheCNS—forexample,themeningesandchoroidplexus—byTcellsisaphysio-logicalpartofimmunesurveillance8,butitalsoseemstohaveanimpactonCNSfunctionbeyonditsroleinthepreventionandcontrolofCNSinfection(BOX1).MuchprogresshasbeenmadeinunderstandingthemoleculardeterminantsthatcontrolthedifferentiationofCD4+TcellsintoseveralspecializedThelper(TH)cellsubsetsintheperipheralimmunecompartment.Owingtotheirexpressionofuniquecombinationsofchemokinereceptorsandintegrins,THcellsubsetsaredifferentiallyrecruitedtospecifictissues.Dependingontheircytokineprofileandfunctionalproperties,thesecellsubetsmaybemoreorlesspotentindrivingimmunopathologicaldamageincertainanatomicalsitesoftheCNS.SimilartoeffectorTcells,forkheadboxP3(FOXP3)-expressingregulatoryT(Treg)cellsarerecruitedtotheCNSdur-inginflammatoryprocesses,andtheyhavecrucialrolesindampeninginflammationandre-establishingtissuehomeostasisintheCNS.Moreover,itisincreasinglyappreciatedthattheCNSharboursCD8+tissue-residentmemoryT(TRM)cellsthatpersistintheCNSparen-chymaaftertheclearanceofviralinfections9,10.Thesecellsprobablyreflectanindivid...
