1、LAKGranzyme BPerforinStromalCellsNK cellPerforinGranzyme BGranulysinTcB cellplasmacellmacrophagePMNeffector TAPCTregFoxp3+/-TH2IL-4,IL-5,IL-6,IL-10,IL-13NKTTH17/THiTH1IL-2,IFN-,TNF-IL-4IL-10IFN-THPAPCDCGITR/AITRTCRCD4CD25CD25CD69CD94NKG2DTCRNK1.1CD244IL-12RTCRCD4IL-23RCD94CD26CD4TCRCD195IL-18RTim3TR
2、ANCETim1CXCR4CD30TCRCD4CCR8FR4 Costimulatory SignalsAntigen PresentationIL-17A,IL-17F,IL-17A/F,IL-22TGF-,IL-10IL-4,IFN-,IL-17(iNKT subset)TNF-IL-8IL-23SurvivalExpansionTGF-+IL-6Differentiation IL-4 IL-15 IL-25 IL-31 IL-33IL-6IL-8TNF-IL-28IL-29IL-27(early)IL-12p70 (+IL-15)TRANCE IL-23(late)T-betGATA3
3、ROR-T,STAT3,STAT4InitiationIL-2,IL-4,IL-27,IFN-,STAT5NegativeRegulationNegative regulationSignal/ActivationDifferentiationSecretionLAK-lymphokine activated killer cellPMN-polymorphonuclear neutrophilKEYMouseHumanApril 2007Compiled by Noosheen Alaverdi&David SehyDesigned by Steven Lee 2007 eBioscienc
4、eFunctionally-Distinct T Cell Lineages:An Emerging DiversityWEB TECH SUPPORT ORDER 888.999.1371 TECH 888.810.6168 FAX 858.642.2046 Overview:The Th1/Th2 Paradigm Expanded:Activated CD4+Th(T helper)cells have been functionally divided into two major subsets,designated as“Th1”and“Th2”populations.First
5、defined by T.Mossman et al.,in 1986,these subsets are generally distinguished by their actions,including their production of specific cytokines and involvement in different types of immune reactions.Th1 cells produce IFN-,IL-2,TNF-,and lymphotoxin and participate in cell-mediated responses to intrac
6、ellular pathogens.Th2 cells produce IL-4,IL-5,IL-6,IL-9,IL-10,and IL-13 and are involved in responses to large extracellular pathogens,such as parasites.Th17 Cells Identified:Recently,IL-17-producing CD4+T cells(Th17 cells)have been identified as a unique subset of Th cells that develops along a pat
7、hway distinct from the Th1-and Th2-cell differentiation pathways.One proposed mechanism is IL-23-dependent,but independent of STAT-1,T-bet,STAT4,and STAT6.The hallmark effector molecules of Th1 and Th2 cells,IFN-and IL-4,respectively,have each been found to negatively regulate the generation of thes
8、e Th17 cells.By a second proposed mechanism,de novo differentiation of Th17 cells in the absence of IL-23 has been demonstrated by treatment of nave CD4 cells with TGF-1 and IL-6,an effect heightened by IL-1 and TNF-.Though absent during the Th17 differentiation,IL-23 is still required for survival
9、and expansion of the Th17 cells.In EAE experiments,adoptive transfer of IL-23-polarized IL-17 effector cells is required for disease progression.Moreover,inhibition of the(negative-regulatory)IFN-signal has been found to lead to enhanced development of pathogenic Th17 effector cells and autoimmune d
10、isease exacerbation.Tregs Defined:Distinct subsets of regulatory CD4,CD8,NKT,and gamma delta T cells are now believed to function to suppress the outgrowth of potentially pathogenic antigen-reactive T cells,controlling tolerance,autoimmunity and immune response to transplanted allografts,allergens,a
11、nd infectious pathogens.The definition and categori-zation of candidate Treg cells has been based largely on their capacity to produce suppressive cytokines,such as IL-4,IL-10,and TGF-.Some IL-10 homologs(e.g.,IFN-family members,such as IL-28,IL-29)have recently been found to prime dendritic cells t
12、o induce proliferation of Foxp3-bearing regulatory T cells.Natural Treg:Referred to as the naturally-occurring Treg population,they execute regulatory function during surveillance of self antigens for prevention of autoimmune response.Inducible Treg:Inducible regulatory T cells are derived from matu
13、re peripheral CD4+CD25-T cells.Ex vivo generation of iTregs has been carried out via treatment of CD4+CD25-T cells by antigen plus IL-10 or TGF-1,by vitamin D3,or by immune suppressive drugs,such as dexamethasone.Emerging Diversity:Expanded subsetting of T cells based on surface receptor,effector ph
14、enotype,and surrogate markers of effector phenotype will undoubtedly continue to elicit greater understanding and appreciation of the complexity of functional roles of an expanding number of distinct T cell lineages.Knowledge of the unique roles of the different T cell subsets in context of immune m
15、ilieu will be essential for our understanding of the implications of their activities in the pathogenesis of a plethora of diseases.CD3/TCR complexMultimericT,thymAntigen recognition,T cell activationT cells recognize antigen/MHC and signal through thisSemin Immunol.3:313.CD455kDa IgSFThym,T sbst,mo
16、no(H),DC sbst(M)TCR coreceptor,MHC II ligand,T diff,HIV receptor(H)Helper T secreting many cytokines to activate B,CTL&macImmunol.Rev.101:39.CD2845kDa,homodimerThym,T and NK CD80 and CD86 receptor,potent T costimulatorTh17 cells are dependent on CD28 signalingNat Immunol.6:1133.CD278/ICOS,H4,AILIM,C
17、RP-140-70kDa IgSFT act,GC TT costim,B7-H2 ligandTh2 diff&expansion,Th17 cells are dependent on ICOS signalingNat Immunol.6:1133.IFN-1mer:20kDa,2/4mers:40/60kDa/by T act,NK&BAntiviral,antiparasitic agent,immuno-modulator for TNegatively regulates Th17 cellsNat Immunol.6:1133.IFN-R,CD119HeterodimerBro
18、adReceptor also present in soluble formComplex of IFNR1 and non-ligand binding IFNR2IL-4,BCDF,BCGF-1&BSF-114kDa/by T,NKT,basophils,mast cells,eosinophilsB prolif/diff,isotype switchNegatively regulates Th17 cellsNat Immunol.6:1133.IL-6,BCSF,BSF-221-28kDa/by activated mono,fibroblasts,endoAcute phase
19、 reaction,neuron developmentWith TGF-promotes diff of Th17 cellsNature.441:235.IL-12R,CD212Oligomer,hemo-poietin receptor superfamilyT act,NKEssential role in the activation and diff of Th1IL-17A20-30kDa homodimer/by T act;also,IL-17 family members in many tissuesPro-inflammatory;enhances expres-sio
20、n of ICAM-1 in fibroblasts;mediates angiogenesisStimulates epithelial,endothelial,or fibroblastic cells to secrete IL-6,IL-8,G-CSF,and PGE2,signature Th17 markerImmunity.24:179.Nature Immunol 6:1133.J.Immunol.175:2374.J.Immunol.172:4503.IL-17A/F37kDa,heterodimerT actRegulates expression of IL-6 and
21、KC;induces IL-8,GM-CSF,Gro-aEffector cytokine of Th17 lineage;regulates inflammatory responsesCell Res.doi:10.1038/cr.2007.35.IL-17B/by pancreas,small intestine,stomachNo binding to IL-17RPromotes production of TNF-and IL-1 in vitroIL-17CInduces TNF-and IL-1IL-17D/by skeletal muscle,lung,brain,adipo
22、se,heartInduces the production of IL-6,IL-8,and GM-CSFPromotes expression of pro-inflammatory genesIL-17F/ML-137kDa,disulfide-linked homodimer/by T act,monocytesInhibits angiogenesis,induces IL-8,GM-CSF,Gro-aPromotes expression of Th1 genes,signature Th17 markerJ Exp Med.203:2271.IL-17R familyBroadC
23、ytokine Growth Factor Rev.14:155.IL-2216kDa,IL-10 familyT actInduces acute phase response,chemo-kines,and metalloproteinases;enhances antimicrobial peptide responsesEffector cytokine of Th17 lineageJ Exp Med.203:2271.IL-23Heterodimer,p19/p40/by DC actSurvival and expansion of Th17 cellsJ.Clin.Invest
24、.116:1218.IL-23RIL-23R/IL-12R1 heterodimer Associates with JAK2 and STAT3Heterodimer complex required for IL-23A signalingCurr Opin Investig Drugs.6:489.IL-25,IL-17E/by BM stroma,polarized Th2,not nave TSignature Th2 effects,increases eosino-phil productionPromotes expression of Th2-like inflammator
25、y genesJ.Immunol.169:443.IL-27Heterodimer EBI3/p28/by APC act(early)Rapid expansion of nave TNegatively regulates Th17 cellsTGF-Homodimer/by many cells including platelets,lymphocytes,monocytesWound healing,broad growth inhibitor of hematopoietic and non-hematopoietic cellsWith IL-6 promotes differe
26、ntiation of Th17 cellsNature.441:231.Tim-3,Havcr2,Timd3(M)Type I TMLate stage CD4+Th1&CD8+Tc1Th1-specific marker,macrophage activationTransport&effector function of Th1,autoim-munity regulationTNF-17kDa TNFSF membrane bound 26kDa/by mac/mono,neutro-phils,CD4+T&NK2/3mers,cytolytic,immune regulationWi
27、th IL-1&IL-12 cofactors induces antigen-specific Th1,inhibition of Th2 responses.CD3/TCR complexsee Table 1CD4see Table 1CD26,THAM,DPP-IV110kDa Type II TMThym,B,NK,T act,epithEctoenzyme,adhesion,T costim,HIV entry(H)Higher on Th1 than Th2,T costimJ.Histochem Cytochem.50:1169.CD94,KP43,Klrd143kDa C-t
28、ype lectinNK,T sbstw/NKG2,inhibits NK functionOn Th1,not Th2,T costimJ.Immunol.169:5382.CD195,CCR5,Cmkbr545kDa TM7SFT sbst,NK,monoMIP-1,&RANTES receptor,R5 HIV coreceptor(H)Predominantly on Th1,w/CD4,IL-6-induced Th1 migrationJ.Immunol.171:4965.Granzyme BSerine protease/by CTL&NK granulesCytolytic,t
29、arget cell deathTh1&Granzyme B+CTLs sensitive to RapamycinJ.Immunol.160:5355.IFN-(H)19-26kDa,23 variants/by mono/mac,fibroblastsAntiviral,antiparasitic,anti-proliferative activitiesHuman Th1 development(without IL-12),IL-18R upregulationJ.Immunol.161:6567.Nat.Immunol.1:65.J.Immunol.165:1933.IFN-1mer
30、:20kDa,2/4mers:40/60kDa/by T act,NK&BAntiviral,antiparasitic agent,immunomodulator for TCellular immunity,intracellular pathogens control via reactive nitrogen intermediatesPNAS.100:15047.Med.Micr.Imm.193:1.IL-2,TCGF15-17kDa/by CD4+T actT,B,NK&LAK prolif,tumor surveillanceInduces IFN-,IL-1,TNF-&TNF-
31、J.Immunol.166:1991.IL-12 p70Heterodimer,p35/p40/by mac&DC actInduces IFN-from T&NKPolarization of nave CD4+to Th1(not absolutely required)Med Microbiol Immunol.193-1.IL-15,IL-T,Th1(M),Th2(H)14-15kDamRNA in muscle,epith&placenta,not/by TNK diff,shares functional similarities with IL-2Mouse:with IL-12
32、 to induce Th1 clones.Human:induces IL-5 production by allergen-specific Th2 clonesJ.Immunol.166:1991.IL-18R,IL-1RrpIL-1R familyTh1,NK sbst,neutrophils&IL-12-stimulated BLow affinity binding to IL-18,high affinity w/IL-18RPro-inflammatory cytokine,enhances innate&specific Th1 responsesJ.Immunol.165:
33、1933.Immunity.16:755.IL-23Heterodimer,p19/p40/by DC actPromotes memory T,correlating with IL-23R,induces IL-17/by memory T actJ.Immunol.171:600.J.Biol.Chem.278:1910.IL-27Heterodimer EBI3/p28/by APC act(early)Rapid expansion of nave TWith IL-12 early trigger of IFN-/by nave CD4+TImmunity.16:755.IL-27
34、R,TCCR,WSX-1Type I cytokineThym,leukocytesTh1 developmentInitial mounting of Th1 response,dispensable for Th1 maintenanceImmunity.16:755.Perforin70kDa/by CTL(Tc1,Tc2)&Th1,NKCytolytic,polymerizes&forms TM channelsPerforin-mediated killing in Tc1&Tc2,FasL-mediated in Th2J.Immunol.165:3058.Tim-3,Havcr2
35、,Timd3(M)Type I TMLate stage CD4+Th1&CD8+Tc1Th1-specific marker,macrophage activationTransport&effector function of Th1,autoimmunity regulationNature 6871:536.TNF-17kDa TNFSF membrane bound 26kDa/by mac/mono,neutro-phils,CD4+T&NK2/3mers,cytolytic,immune regulationWith IL-1&IL-12 cofactors induces an
36、tigen-specific Th1,inhibition of Th2 responsesJ.Immunol.160:1708.TRANCETNFSF/by T act,memory TRANK LigandPreferentially on activated Th1,induces IL-12J.Immunol.166:270.CD3/TCR complexsee Table 1CD4see Table 1CD30,Ki-1105-120kDa TNFRSF,soluble formB act&T actCD153 Ligand,lymphocyte prolifCorrelation&
37、lack of correlation with Th2FASEB J.9:81.J.Immunol.156:1387.CD81,TAPA-126kDa TM4SFBroadw/CD19/CD21 on B,T costimIL-4 synthesis by B&Th2 polarizationInternational Immunol.14:513.CD184,CXCR4,Fusin,Cmkar4TM7SFNave T,T act,NKCoreceptor X4 HIV,SDF-1&MIP-2 receptorVariable levels on Th2,not on polarized T
38、h1(only on short-term culture+IL-4)J.Immunol.160:4153.CD197,CCR7,EBl1,Cmkbr745kDa TM7SFT sbst,DC6Ckine&MIP-2 receptorCCR7+memory T inducers of Th2 bias in CD4+TJ.Immunol.112:274.CDw198,CCR8,Cy6,Cmkbr8TM7SFThym,T,monoReceptor for I-309,TARC,MIP-1,thym apoptosisTh2 polarization&chemotaxisJ.Immunol.161
39、:547.CD278,ICOS,H4,AILIM,CRP-140-70kDa IgSFT act,GC TT costim,B7-H2 ligandTh2 diff&expansionJ.Immunol.167:1996.IgDIgSFMature BB activationInduces strong CD4+Tdependent IgG1/E&IL-4 responsesCurr Protocol in Immunol.Unit 6.28.IL-4(M),BCDF,BCGF-1&BSF-114kDa/by T,NKT,basophils,mast cells,eosinophilsB pr
40、olif/diff,isotype switchTh2 cytokine,contributes to pathogenesis of allergy;polarized with IFN-(M),sometimes with IFN-(H)Ann.Rev.Immunol.15:505.Adv.Exp.Med.Biol.409:343.IL-5,EDF,BCGFII,TRFhomodimer 32-34kDa/by T&NKTEosinophil diff,Ig productionTh2 cytokine,promotes CTLEur.J.Immunol.17:1743.Immunolog
41、y.63:277.IL-6,BCSF,BSF-221-28kDa/by activated mono,fibroblasts,endoAcute phase reaction,neuron developmentTh2 cytokine,B diff&T activation factorFASEB J.4:2860.Ann.Hematology 62:203.IL-10(M),CSIF18kDa/by mono lymphocytesImmune regulationTh2 cytokine,inhibits IFN-,IL-2&TNF-in Th1,restricted to Th2 ce
42、lls(M),/by&inhibits Th1&Th2(H)J.Immunol.150:353.Immunol Today 13:198.IL-13(M)11-12kDa/by T act,Th2(M),basophils(H)B maturation,inhibit mac&nitric oxide productionTh2 cytokine,reduces IL-1/6/8/10/12,MIP-1&MCP in response to IFN-or LPSImmunol Today 15:19.IL-15(H)see Table 2IL-25,SF20,IL-17E/by BM stro
43、ma,polarized Th2,not nave TSignature Th2 effects,increases eosino-phil production and inflammationMediates effect through IL-4,IL-5 and IL-13JEM 203:809.IL-3124kDa,four-helix bundle,alpha-heli-cal cytokine familyCD4+T act and at lower levels in CD8+T;prefer-entially by Th2Activates STAT1,STAT3,and S
44、TAT5,but not STAT6Promotes allergic skin disorders and regulates other allergic diseases,such as asthmaNat.Immunol.5:752.IL-3332kDa,IL-1 family,processed by cas-pase 1 to 12kDa and 18kDaSmooth muscle,airway epith,fibroblasts,kerati-nocytesProinflammatory cytokine and intracel-lular nuclear factor wi
45、th transcriptional regulatory properties;binds ST2,induces IL-5 and IL-13Involved in the pathogenesis of allergic diseases,such as asthmaImmunity.23:461.Tim-1,Havcr1,Timd1(M)IgSFT actHepatitis A virus receptorRegulation of atopic diseases,Th2-driven responsesSpringer Semin Immun.25:335.J.Immunol.172
46、:7169.NameMW/StructureCellular ExpressionReported FunctionRole in Th17ReferenceStructure and FunctionTable 1:Th17-Related MarkersNameMW/StructureCellular ExpressionReported FunctionRole in Th1ReferenceTable 2:Th1-Related MarkersNameMW/StructureCellular ExpressionReported FunctionRole in Th2Reference
47、Table 3:Th2-Related MarkersKEY/by:secreted by,act:activated,costim:costimulation,diff:differentiation,endo:endothelium,epith:epithelium,GC:germinal center,H:human,M:mouse,mac:macrophages,mono:monocytes,prolif:proliferation,sbst:subset,Thym:thymus,TM:transmembrane,w/:associates witheBioscience Produc
48、tsCell Surface MarkersCommon and novel cell surface markers.AntigenMouseHumanCD1d 1B1-CD3-OKT3,UCHT1,HIT3aCD3e145-2C11,17A2-CD4 GK1.5,RM4-5,RM4-4 OKT4,RPA-T4 CD8 53-6.7,eBioH35-17.2,CT-CD8b OKT8,RPA-T8,HIT8a CD25 PC61.5,eBio7D4,eBio3C7 BC96 CD26-2A6 CD28 37.51CD28.6(blocking),CD28.2(costimulatory)CD
49、30 mCD30.1-CD56-MEM188 CD62L MEL-14 DREG56 CD69 H1.2F3 FN50 CD81 Eat-2-CD94 18d3 DX22 CD103 2E7B-Ly7 CD161/NK1.1 PK136-CD244 eBio244F4 eBioPP35,eBioDM244,eBioC1.7CD254/TRANCE IK22/5 MIH23,MIH24CD278/ICOS 7E.17G9,C398.4A,15F9ISA-3 GITR/AITR DTA-1 eBioAITR GITR-L/AITR-L eBioYGL386 eBioAITR-L HLA-ABC-W
50、6/32 HLA-DR-LN3 IgD 11-26c,polyclonal(activating)-MHC class I 34-1-2S,28-14-8-MHC class II NIMR-4,M5/114.15.2(I-A/I-E),14-4-4S(I-Ek)-NKG2D CX5(blocking),MI6(blocking),A10(activating),C7(blocking)1D11(activating),5C6(activating)T-bet eBio4B10,eBio39D eBio4B10,eBio39D TCR/-IP26 TCRbH57-597-TCR/GL3,UC7