FOCUS|ReviewARticlehttps://doi.org/10.1038/s41590-018-0120-41DepartmentofNeurology,YaleSchoolofMedicine,NewHaven,CN,USA.2DepartmentofImmunobiology,YaleSchoolofMedicine,NewHaven,CN,USA.*e-mail:margarita.dominguez-villar@yale.edu;david.hafler@yale.eduMorethan20yearsaftertheir‘re-discovery’,regulatoryTcells(Tregcells)haveemergedasanimportantcomponentinunderstandingoftheimmuneresponsetopathogensandthemechanismsofperipheraltolerancethatcontrolthedevelopmentofallergiesandautoimmunediseases.Inmiceandhumans,TregcellsarecharacterizedbyhighexpressionofthecytokineIL-2receptorα-chain(CD25)andexpressionofthetranscriptionfactorFoxp3,whichisrequiredfortheirdevelopment,functionandstability1–4.Inhumans,asCD25isalsoexpressedbyactivatedCD4+Tcells,absenceoftheIL-7receptorα-chain(CD127)isusedasamarkercomplemen-tarytoCD25tomorepreciselyidentifyhumanTregcells5.Moreover,numeroussurfacereceptorshavebeendescribedthatarevariablyspecificfordefinedTregcellsubsets,indicativeoftheheterogeneityofthispopulation6.Tregcellscanbebroadlyclassifiedintotwogroupsonthebasisoftheirdevelopmentalorigin.ThymicTregcells(tTregcells),alsoknownas‘naturalTregcells’,aregeneratedinthethymusasasepa-ratelineageatthestageofCD4+single-positivethymocytesandarethoughttoshowenrichmentforTcellantigenreceptors(TCRs)withhighaffinityforselfpeptides7.Althoughthedetailsoftheirsuppres-sivemechanismsarestillnotcompletelyunderstood,andthesemech-anismsaremostprobablydependentonthemicroenvironmentandthetargetpopulationtobecontrolled,ingeneralthesecellsperformtheirfunctionbothbycell-contactmechanismsthatinvolvespecificcell-surfacereceptorsandbythesecretionofinhibitorycytokinessuchasIL-10,TGF-βandIL-357.InducedTregcells(iTregcells)developfromconventionalCD4+TcellsintheperipheryafterantigenencounterandinthepresenceofspecificfactorssuchasTGF-βandIL-28.Sofarthereis(are)nodefinitiveproteinmarker(s)thatdistinguish(es)betweenthesetwoTregcellpopulationsinvitroorinvivo,althoughthereareimportantdifferencesintheirepigeneticsignatures,...
