114 539 : TCR MHC MHC II CD4Th IFN γ Th1 IL 4 Th2 IL 17 Th17 TGFβ/IL 10 Treg IL 9 Th9 IL 22 Th22 IL 21 Tfh follicular helper MHC Ia CD8T IL 2 CD4/CD8T innate T cells MHC Ib NK TCR NKT γδ MAIMHC Ib CD8 : CD4Th CD8 1 T major histocompatibility complex : MHC TCR TCR α β γ δ TCR αβ TCR γδ TCR CD3 CD3 γ δ ε ζ FcRγ CD4 CD8 MHC CD4 MHC CD8 MHC CD28 CD80 BCD86 α α 14q11 12 14C D Cα kb Jα Vα Jα
114 540 2011 Vα β β q32 35 Cβ Dβ Jβ Jβ1 Jβ2 Jβ Vβ Vβ Vβ Vβ3 Vβ5 Vβ8 Vβ Vβ Dβ1 500kb Vβ Cβ Vβ γ γ p15 160kb Cγ Jγ Vγ Cγ1 S S Cγ2 Jγ Cγ1 Cγ2 Jγ1 Vγ Vγ1 Vγ Vγ2 Vγ3 Vγ4 Vγ Vγ γ A2 3 Cγ Jγ Cγ3 Vγ Vγ1 Vγ2 Vγ3 Jγ4 cγ4 Jγ2 Cγ2 Jγ3 Cγ3 Jγ1 Cγ1 Vγ4 Vγ5 Vγ6 Vγ7 Vγ Vγ2 Jγ2 Cγ2 Vγ Jγ Cγ δ δ α Cα 98kb Jα Cδ Jδ Dδ Cδ Vδ Vα Vδ Vδ3 δ δ Jα Cδ Jδ Dδ Vδ Vα Vδ5 Vδ3 Cδ TCR TCRαβ MHC Vα Vβ CDR MHC α TCRVα Vβ CDR γδ TCR γδ TCR Cγ1 40kd γ δ S S TCR γδ / Cγ2 γ δ S S γ 55kd 40kd CDR CDR 3 γδ TCR S S Vγ2 Jγ2 Cγ2 γ Cγ1 γδ TCR 38kd Vγ5 Jγ1 Cγ1 γ 48kd Vδ1 D Jδ2 Cδ δ dendritic epidermal cells ; DEC 36kd γ 46kd δ γ Vγ4 Jγ1 Cγ1 δ Vδ5 Vδ7 Dδ Jδ Cδ CD4 CD8 CD4 CD8 35kd Vγ6 Jγ1 Cγ1 γ 48kd Vδ1 Dδ Jδ2 Cδ δ γδ TCR γδ TCR
114 541 TCR Vγ Vδ CDR Vγ V J VδVDJ CDR3 γδ TCR δ CDR3 γ CDR3 γδ TCR MHC T 10 T22 γδ T22 γδ TCR Dδ CDR3 germ line TCR α β γ δ TCR CD3γδε ζ FCRγIγ CD3 ITAM immunoreceptor tyrosine based activation motif CD4 CD8 PTK lck ITAM ITAM PTK zeta associated protein 70 ZAP70 ZAP 70 LAT Grb2/ SOS Ras GTP Raf1 Raf1 MKK1 ERK1/2 MAP Fos ZAP 70 SLP 76 SLP 76 Vav Rac Jun Fos Jun AP 1 IL 2 ZAP 70 LAT SLP76 Tec Itk Rlk phospholipase Cγ1 PIP2 DG PIP2 PKC DG Ca Ca NF AT IL 2 SLP76 ADAP VASP PKCθ CARMA 1 /CARD11 Bcl 10 NFκb TCR Csk SHP 2 PAG Gab2 SLAM SAP Cbl Dok1/2 CD28 CD28 CD80 CD86 PI3k Grb2/SOS MKK1 ERK1/2 MAP :anergy TCR clonal deletion CD28 CTLA 4 CD152 CD28 SHP2 ICOS B7RP1 PIK PD 1 BTLA 1 ITIM immunoreceptor tyrosine based inhibitory motif SHP 2 2 T CD4Th II CD4Th IFN γ γ Th1 IL 4Th2 IL 17 Th17 TGFβ/IL 10 Treg IL 9 Th9 IL 22 Th22 IL 21 Tfh follicular helper Th1 Th1 γifn TNF α/β γifn Th1
114 542 2011 IL-12 Pattern recognition receptor Th1 DC T TGF- T-bet IFN- Th1 IL-2 Retinoic acid IFN- TNF Treg DC T FoxP3 Treg IL-10 TGF- MHC/Ag TCR Th2 DC T GATA-3 IL-4 TSLP Th2 Th9 IL-4 IL-5 IL-13 IL-9 Th17 IL-6/TGF- Tfh IL-21 DC T IL-23 RoR t Th17 IL-17A IL-17F IL-22(AhR) 1 IL12 TH1 NK Th IFN γ Th1 Th1 T bet T bet IFN γ IL12 Rβ2 IFN γ Th1 Th2 Th2 IL 4 IL 5 IL 13 IL 10 Th2 NKT Th2 IL 4 Th2 Th2 GATA3 IL 4 IL4R STAT6 GATA3 Th2 Th17 Th17 IL 17A IL17F G CSF CXCL8 TGF β IL 6 Th17 RORγt RORα IL 6 IL 21 IL 2 IL 1 Th17 Il 12 IL 23 Th17 Th17 Th17 IL 22 IL 10 AhR aryl hydrocarbon receptor IL 22 Th Th22 Treg Treg naturally occurring Treg ntreg inducible Treg itreg TGF β Treg
114 543 FoxP3 TGF β FoxP3 Th17 RORγt IL 6 Foxp 3 Retinoic acid Treg Treg IL 10 TGF β CTLA 4 FoxP3 itreg IL 10 Foxp3 CD4 Tr1 Tfh IL 10 IL 21 CXCR5 IL 21 Bcl 6 Th9 IL 9 Th Th2 TGF β in vitro Th2 Th22 Th17 IL 17 RORγt CD8 CD8 MHC IL 2 CD4Th IL 2 CD8 Fas/Fas L DNA CD8 CD8 CD4 FasL Fas Fas CD8 IFN γ TNF β Th1 CD8 CD8T CD44 CD62L CD127 IL 7R CD44 CD62L CD127 IL 7R IL 2 CD44 CD62L CD127 IL 7R IL 2 IL 12 T bet Eomoes Blimp 1 short lived effector CD8T IL 2 IL 12 IL 7Ra T bet Enomose Bimp 1 long lived memory CD8T cells CD8 CD8 IL 15 IL 7 MHC conventional T cells innate T cells MHC Ib NK TCR TEC SLAM/SAP PLZF CD8 MHC CD8
114 544 2011 IL-2 IL T IL-2 IL 2 CD8 TEC(+) CD4T NKT CD4-CD8- CD4+CD8+ TEC(+) TEC(-) TEC(+) Innate CD4T CD8T T Innate CD8T 3 Innate T TCR TEC Rtk /RlkSLAM innate T
114 545 γδ γδ αβ γδ Vγ9/Vδ2 isopentenyl pyrophosphate F1 ATPase apolipoprotein A1 Vδ1T MHC MIC A MIC B MHC T10 T22 γδ γδ αβ IFN γ IL 17 CD27 CD122 NK1 1 PLZF SLAM/SAP IFN γ IL 4 IL 15 IL 17 γδ CD27 CD25 IL 17 γδ NKT NKT CD4 CD8 CD4 CD8 Vα14 Jα18 Vβ8 Vβ2 Vβ7 TCR Vα24/Vβ11CD1d α Ehrlichia Sphingomonas LPS NK CD1 CD1d Vα3 2 Jα9 Vβ8 TCR NKT CD4 CD8 CD1d SLAM PLZF NKT IL 4 IFN γ MHC Ib CD 1 CD1a b c CD4 CD8 CD8 perforin/granulysin MHC Ib H2 M3 TAP N formylated peptides H2 M3 MHC Ib CD8 MALT MAIT Mucosal associated invariant T cells ; MAIT cells NKT Vα7 2Vα19 Jα33 MHC MR1 MAIT MAIT CD4 CD8 CD4 Th CD8 MHC CD4 CD8 T TCR TEC CD4 CD8 DP SLAM CD4 CD8 CD44 CD62 CD122 NK1 1 PLZF IL 4 IFN γ TNF β Th1 :...,,, ; :. Wan YY : Multi tasking of helper T cells. Immunology 2010 ; 130 : 166 171. Littman DR, Rudensky AY : Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010 ; 140 : Murphy KM, Stockinger B : Effector T cell plasticity : flexibility in the face of changing circumstances. Nat Immunol 2010 ; 11 : Zhu J, Yamane H, Paul WE : Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010 ; 28 :
114 546 2011 445 489. Belz GT, Kallies A : Effector and memory CD8 Tcell differentiation : toward a molecular understanding of fate determination. Curr Opin Immunol 2010 ; 22 : 279 285. Berg LJ : Signalling through TEC kinases regulates conventional versus innate CD8 T cell development. Nat Rev Immunol 2007 ; 7 : 479 485. Prince AL, Yin CC, Enos ME, et al : The Tec kinases Itk and Rlk regulate conventional versus innate T cell development. Immunol Rev 2009 ; 228 : 115 131. Felices M, Yin CC, Kosaka Y, et al : Tec kinase Itk in gammadeltat cells is pivotal for controlling IgE production in vivo. Proc Natl Acad Sci USA 2009 ; 106 : 8308 8313. Schwartzberg PL, Mueller KL, Qi H, et al : SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Immunol 2009 ; 9 : 39. Bonnevillel M, O Brien RL, Born WK : γδ T cell effector functions : a blend of innate programming and acquired plasticity. Nat Rev Immunol 2010 ; 10 : 467 478. Verykokakis M, Boos D, Bendelac A, et al : Inhibitor of DNA Binding 3 Limits Development of Murine Slam Associated Adaptor Protein Dependent Innate γδ T cells. PLoS One 2010 ; 5 : e9303. Kreslavsky T, Savage AK, Hobbs R, et al : TCR inducible PLZF transcription factor required for innate phenotype of a subset of gamma delta T cells with restricted TCR diversity. Proc Natl Acad Sci USA 2009 ; 30 : 12453 12458. Cua DJ, Tato CM : Innate IL 17 producing cells : the sentinels of the immune system. Nat Rev Immunol 2010 ; 10 : 479 489. Kovalovsky D, Uche OU, Eladad S, et al : The BTB zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat Immunol 2008 ; 9 : Godfrey DI, Stankovic S, Baxter AG : Raising the NKT cell family. Nature Immunology 2010 ; 11 : 197 206. Weinreich MA, Odumade OA, Jameson SC, et al : T cells expressing the transcription factor PLZF regulate the development of memory like CD8 T cells. Nat Immunol 2010 ; 11 : 709 716.