Th1细胞的分化

TheTh1Subset231theT-boxfamilyoftranscriptionfactors,isinducedinnaiveCD4+TcellsinresponsetoantigenandIFN-γ.IFN-γalsoactivatesthetranscriptionfactorSTAT1,whichinturnstimulatesexpressionofT-bet.T-betthenpromotesIFN-γproductionthroughacombinationofdirecttran-scriptionalactivationoftheIFNGgeneandbyinducingchromatinremodelingoftheIFN-γpromoterregion.TheabilityofIFN-γtostimulateT-betexpressionandtheabilityofT-bettoenhanceIFN-γtranscriptionsetupapositiveamplificationloopthatdrivesdifferentiationofTcellstowardtheTh1phenotype.IL-12contributestoTh1commitmentbybindingtoreceptorsonantigen-stimulatedCD4+TcellsandactivatingthetranscriptionfactorSTAT4,whichfurtherenhancesIFN-γproduction.bythedevelopmentofTh2cells,andthecytokinesproducedbythesecellsareimportantforcombatinghelminths.Similarly,Th17responsesareinducedbysomebacteriaandfungiandaremosteffectiveatdefendingagainstthesemicrobes.ThegenerationandeffectorfunctionsofthesedifferentiatedTcellsareanexcellentillustrationoftheconceptofspe-cializationofadaptiveimmunity,whichreferstotheabilityoftheimmunesystemtorespondtodifferentmicrobesinwaysthatareoptimalforcombatingthosemicrobes.Withthisbackground,wewillproceedtoadescriptionofthedevelopmentandfunctionsofeachsubset.THETh1SUBSETTheIFN-γ–producingTh1subsetisinducedbymicrobesthatareingestedbyandhaveevolvedtosurviveandreplicatewithinphagocytes,andisthemajoreffectorTcellpopulationinphagocyte-mediatedhostdefense.Th1cellswerethefirstdefinedsubsetofhelperTcellsshowntomediatecellularimmunityagainstpathogensthatsurviveinsidephagocytes.DevelopmentofTh1CellsTh1differentiationisdrivenmainlybythecytokinesIL-12andIFN-γandoccursinresponsetomicrobesthatactivatedendriticcells,macrophages,andNKcells(Fig.10.5).Thedifferentiationofantigen-activatedCD4+TcellstoTh1effectorsisstimulatedbymanyintracel-lularbacteria,suchasListeriaandmycobacteria,andbysomeparasites,suchasLeishmania,allofwhichinfectdendriticcellsandmacrophages.Th1differentiationisalsostimulatedbyvirusesandbyproteinantigensadministeredwithstrongadjuvants.Acommonfeatureoftheseinfectionsandimmunizationconditionsisthattheyelicitinnateimmunereactionsthatareassociatedwiththeproductionofcertaincytokines,includingIL-12,IL-18,andtypeIinterferons.AllofthesecytokinespromoteTh1development;ofthese,IL-12isprob-ablythemostpotent.IL-18synergizeswithIL-12,andtypeIinterferonsmaybeimportantforTh1differentia-tioninresponsetoviralinfections,especiallyinhumans.ManymicrobesstimulateNKcellstoproduceIFN-γ,whichisitselfastrongTh1-inducingcytokineandalsoactsondendriticcellsandmacrophagestoinducemoreIL-12secretion.AfterTh1cellshavedeveloped,theysecreteIFN-γ,whichpromotesmoreTh1differentiationandthusamplifiesthereaction.Inaddition,IFN-γinhib-itsthedifferentiationofnaiveCD4+TcellstotheTh2andTh17subsets,thuspromotingthepolarizationoftheimmuneresponseinonedirection.TcellsmayfurtherenhancecytokineproductionbydendriticcellsandmacrophagesbyvirtueofCD40LonactivatedTcellsengagingCD40ontheAPCsandstimulatingIL-12secretion.IFN-γandIL-12stimulateTh1differentiationbyinducingandactivatingthetranscriptionfactorsT-bet,STAT1,andSTAT4(seeFig.10.5).T-bet,amemberofDendriticcellMicrobesNaiveTcellNKcellIFN-γIFN-γIFN-γIFN-γIL-12IL-12MacrophageSTAT4STAT1T-betAmplificationTh1cellsFIGURE10.5DevelopmentofTh1cells.IL-12producedbydendriticcellsandmacrophagesinresponsetomicrobes,includingintracellularmicrobes,andIFN-γproducedbyNKcells(allpartoftheearlyinnateimmuneresponsetothemicrobes)activatethetranscriptionfactorsT-bet,STAT1,andSTAT4,whichstimulatethedifferentiationofnaiveCD4+TcellstotheTh1subset.IFN-γproducedbytheTh1cellsamplifiesthisresponseandinhibitsthedevelopmentofTh2andTh17cells.