Effector and Memory T Cell Differentiation.pdf

SnapShot:Effector and Memory T Cell DifferentiationMatthew E.Pipkin and Anjana RaoDepartment of Pathology,Harvard Medical School,Boston,MA 02115,USASee online version for legend and references.606 Cell 138,August 7,2009 2009 Elsevier Inc.DOI 10.1016/j.cell.2009.07.020 606.e1 Cell 138,August 7,2009 2009 Elsevier Inc.DOI 10.1016/j.cell.2009.07.020 SnapShot:Effector and Memory T Cell DifferentiationMatthew E.Pipkin and Anjana RaoDepartment of Pathology,Harvard Medical School,Boston,MA 02115,USAThe differentiation of T cells is an ideal system to study the molecular basis of lineage specification in mammalian cells.Upon stimulation with antigen during infection or inflammation,naive peripheral T cells differentiate into various types of effector T cells with specific immune functions.Naive CD4+T cells differentiate into at least four subsets(lineages)of T helper(Th)cells:Th1,Th2,Th17,or“induced”regulatory T cells(iTregs).Each subset is distinguished by the cytokines that they produce(Ansel et al.,2006;Lee et al.,2006;Zhou et al.,2009).Naive CD8+T cells differentiate into effector cytolytic T lymphocytes(CTLEff)that kill infected host cells using the pore-forming protein perforin and serine esterases called granzymes(Cruz-Guilloty et al.,2009).Alternatively,naive CD8+T cells can differentiate into memory CTLs(CTLMem)that survive long-term and protect the host from reinfection(Kaech and Wherry,2007).T cell differentiation is in large part determined by signals from the environment and is shaped by numerous feedback and feed-forward loops(bold arrows)that modulate and reinforce the direction in which differentiation proceeds(Singh,2007).Transcription factors(boxes)play a key role in this process by forming networks in which they reinforce or oppose each others actions.This SnapShot illustrates the differentiation pathways for several of the best characterized T cell subsets.NaiveThe transcription factor ThPok and transcription factors of the Runx family act in an antagonistic fashion to specify the development of naive CD4+and CD8+T cells that emigrate from the thymus and colonize peripheral lymphoid organs(Taniuchi,2009).Antigen primingUpon encountering antigen and with costimulation by antigen-presenting cells,naive T cells initiate a generic transcription program called priming(thin black lines)that depends on the activation of widely expressed,latent transcription factors including NFAT,NF-B,and AP-1(Fos-Jun).These,in turn,induce expression or activation of secondary transcription factors such as the early growth response(Egr)proteins(not depicted).They also induce expression of the cytokine interleukin-2(IL-2)and the and chains of the IL-2 receptor(IL-2R).Binding of IL-2 to its receptor activates the Stat5 transcription factor.In certain settings,the transcription factors Blimp-1 and Bcl6 are induced and counteract each others expression(Martins and Calame,2008;Johnston et al.,2009).During this phase,T cells also promiscuously activate low-level transcription of most“lineage-specific”genes(not depicted).Such genes include those encoding the T-bet and Gata3 transcription factors that impose Th1 and Th2 lineage specification,respectively.T-bet and Gata3 are both transcribed early in activated T cells,but in the presence of the cytokine IL-4 that drives Th2 dif-ferentiation,Gata3 expression is sustained whereas T-bet expression is silenced,thus reinforcing Th2 lineage commitment.Cytokine programming and stabilization of the effector phenotypePrimed T cells quickly fall under the control of the cytokine environment.Cytokines program transcription factor networks that stabilize the phenotype and function of differentiating CD4+T cells by driving chromatin modifications that activate lineage-specific and inactivate lineage-inappropriate genes(Ansel et al.,2006;Grogan et al.,2001;Lee et al.,2006).Key lineage-specific transcription factorsT-bet for Th1 cells,Gata3 for Th2 cells,RORt for Th17 cells,and Foxp3 for regulatory T cellsare distinguished by the fact that their ectopic overexpression in differentiating T cells induces“reprogramming”of those cells to the lineage that they control,even in the presence of cytokines that ordinarily program a different lineage.These lineage-specifying factors cooperate with stimulation-induced transcription factors through direct physical interactions(black lines without arrows)to mediate their effects(Ansel et al.,2006;Zhou et al.,2009).Less is known about the transcriptional networks that program CD8+T cell differentiation into effector and memory CTLs,partly because most experiments have been performed in mice infected with model pathogens(Kaech and Wherry,2007).Many of these studies compared wild-type mice with mice carrying disrupted genes.Although genetic analyses can undoubtedly show that a missing gene product has a role in the development of effector or memory CTLs,such analyses cannot deter-mine whether the role is direct or indirectadditional epistatic and biochemical analyses are needed,preferably using simplified cell-culture systems such as those used to examine CD4+T cell differentiation.Such systems have helped to clarify that the transcription factor Runx3 is central to programming the function of CTLs,and that T-bet and Eomesodermin(Eomes)are induced in response to distinct signals and have distinct as well as redundant functions(Cruz-Guilloty et al.,2009).Effector function after re-encounter with antigenEarly transcription factors act again,often cooperating with lineage-specific transcription factors at lineage-specific effector genes whose chromatin structure has been remodeled during differentiation for rapid,high-level transcriptional induction(Ansel et al.,2006).AbbreviationsCytokines and receptors:Interleukin(IL-2,IL-4)and receptors(IL-2R,IL-4R,IL-6R,IL-12R,IL-21R,IL-23R);Interferon gamma(IFN-);transforming growth factor (TGF-).Transcription factors:T-box expressed in T cells(T-bet);signal transducer and activator of transcription(Stat)1,3,4,5,6;H2.0-like homeobox(Hlx);Growth factor independent 1(Gfi-1);GATA-binding protein 3(Gata3);retinoic acid receptor related orphan receptor gamma t(RORt)and alpha(ROR);recombination signal binding protein for immunoglobulin kappa J region(RBPJ);interferon regulatory factor 4(IRF-4);nuclear factor of kappa light polypeptide enhancer in B cells(NF-B);nuclear factor of activated T cells(NFAT);similar to mothers against decapentaplegic(Smads)are TGF-activated transcription factors;forkhead box P3(Foxp3);B lymphocyte induced maturation protein 1(Blimp-1);B cell leukemia/lymphoma 6(Bcl6);T-box factor Eomesodermin(Eomes);inhibitor of DNA binding 2(Id2);Kruppel like factor 2(Klf2);musculoaponeurotic fibrosarcoma(c-maf)proto-oncogene;zinc finger and BTB domain containing 7B(ThPok);Runt related transcription factor 3(Runx3).RefeRencesAnsel,K.M.,Djuretic,I.,Tanasa,B.,and Rao,A.(2006).Regulation of Th2 differentiation and Il4 locus accessibility.Annu.Rev.Immunol.24,607656.Cruz-Guilloty,F.,Pipkin,M.E.,Djuretic,I.M.,Levanon,D.,Lotem,J.,Lichtenheld,M.G.,Groner,Y.,and Rao,A.(2009).Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs.J.Exp.Med.206,5159.Grogan,J.L.,Mohrs,M.,Harmon,B.,Lacy,D.A.,Sedat,J.W.,and Locksley,R.M.(2001).Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets.Immunity 14,205215.Johnston,R.J.,Poholek,A.C.,Ditoro,D.,Yusuf,I.,Eto,D.,Barnett,B.,Dent,A.L.,Craft,J.,and Crotty,S.(2009).Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.Science.Published online July 16,2009.10.1126/science.1175870.Kaech,S.M.,and Wherry,E.J.(2007).Heterogeneity and cell-fate decisions in effector and memory CD8(+)T cell differentiation during viral infection.Immunity 27,393405.Lee,G.R.,Kim,S.T.,Spilianakis,C.G.,Fields,P.E.,and Flavell,R.A.(2006).T helper cell differentiation:regulation by cis elements and epigenetics.Immunity 24,369379.Martins,G.,and Calame,K.(2008).Regulation and functions of Blimp-1 in T and B lymphocytes.Annu.Rev.Immunol.26,133169.Singh,H.(2007).Shaping a helper T cell identity.Nat.Immunol.8,119120.Taniuchi,I.(2009).Transcriptional regulation in helper versus cytotoxic-lineage decision.Curr.Opin.Immunol.21,127132.Zhou,L.,Chong,M.M.,and Littman,D.R.(2009).Plasticity of CD4+T cell lineage differentiation.Immunity 30,646655.