OpinionRegulatoryImmuneMechanismsbeyondRegulatoryTCellsGustafChristoffersson1andMatthiasvonHerrath2,3,*Inautoimmunity,aggressiveimmuneresponsesarecounteractedbysuppres-siverejoinders.Forinstance,FOXP3-expressingregulatoryTcells(Tregs),haveshownremarkableeffectsinlimitingautoimmunityinpreclinicalmodels.How-ever,earlyresultsfromhumanTregtrialshavenotbeenaspositive.Here,wehighlightquestionssurroundingTregtransfersasputativetreatmentsforautoim-munity.Wediscusswhetherlackofantigenicrecognitionmightbekeytoshiftingcellsfromcontributingtoanaggressiveautoresponse,tobeingpartofaregula-torynetwork.Moreover,wearguethatidentifyingthephysiologicalrangeofimmunosuppressionofTregsmighthelppotentiatetheirefficacy.WeproposewideningtheviewonimmunoregulationbyconsideringtheparticipationofCD8+Tregsinthisprocess,whichcouldhavemajorimplicationsinautoimmunity.ImmuneRegulationandAutoimmunityOurimmunesystemworksinabalance-scalefashion.Immuneresponsesagainstinvadingpath-ogens,tumorcells,andevenhealthycells(i.e.,autoimmunity)ononearmofthescalearealwaysaccompaniedbyanopposingresponseontheotherarmofthescale.Undernormalcircum-stances,thisbalancesouttoanadequatereactiontoeliminatethethreatwhilelimitingcollateraldamage.Onoccasionswheretheaggressiveresponseisnotsufficientlymetwithregulatorymechanisms,autoimmunitymayoccur,andininstanceswherethebalancefavorsimmunosup-pression,cancerscanthrive.InthisOpinion,wearguethatthereisaneedtowidentheviewonimmuneregulationandinvolveotherimmunecellsubsetsandmechanismstothecommonlyper-ceivedconceptsofregulatoryTcells(Tregs).WeprovideabriefoverviewonTregs,theirmech-anismsofaction,clinicalfindings,andprovidesomehistoricandrecentexamplesofstudiesonimmuneregulationexertedbyCD8+Tcells.Wesuggestintensifyingstudiesonthesenewconceptstofindpossiblenewroutesfortappingintoinherentregulatorymechanismsinthetreat-mentofautoimmunediseases.LimitstoOurKnowledgeofImmuneRegulationinAutoimmunityAutoimmunityisthephenomenonbywhichtheimmunesystemrespondsagainstanorganism’sownhealthyce...
