T lymphocyte(2) Nat Rev Immunol, September 2008 Vol 8 No 9

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1 T lymphocyte(2) Nat Rev Immunol, September 2008 Vol 8 No 9 ustcwhm@ustc.edu.cn 1

2 3 The Development of T Lymphocytes in Thymus 3.1 The stages of thymocytes maturation Double negative thymocytes Double positive thymocytes Single positive thymocytes 3.2 T-cell receptor gene rearrangements and receptor expression 3.3 positive selection of T cell 3.4 negative selection of T cell 2

3 T 细胞的胸腺发育 MHC I/II β-selection Commitment Specification T NK DC MΦ B MHC-peptide MHC-peptide T-CELL DEVELOPMENT AND THE CD4 CD8 LINEAGE DECISION Nature Reviews Immunology 2; (2002) 3

4 T 细胞的胸腺发育路线图 Nat Rev Immunol,2008 Vol 8 No 11:788 DN---TCRβ---pre-TCR --CD8+CD4+--SP β-selection pre TCR DP positive selection 4

5 阳性选择模型 1 ( 随机选择模型 ) Classical models of CD4/CD8- Lineage choice. a The stochastic selection model postulates that positive-selecting T-cell receptor (TCR) signals randomly terminate the expression of one or the other co-receptor molecule, resulting in the generation of short-lived intermediate cells, which undergo programmed cell death unless they are rescued by a second TCR signal. Because the TCR-mediated rescue signal requires TCRs and co-receptors that are matched, 50% of positively selected thymocytes will fail to survive and mature. Nat Rev Immunol,2008 Vol 8 No 11:788 5

6 阳性选择模型 2 ( 强弱信号模型 ) b The strength-of-signal instructional model postulates that weak TCR signals terminate Cd4 transcription, whereas strong TCR signals terminate Cd8 transcription. Signalling by CD8 and MHC class I-restricted TCRs is weak and results in mature CD8+ T cells, whereas signalling by CD4 and MHC class II restricted TCRs is strong, which results in mature CD4+T cells. Nat Rev Immunol, 2008 Vol 8 No 11:788 6

7 阳性选择模型 3 ( 持续信号模型 ) c The duration-of-signal instructional model postulates that short and/or weak TCR signals terminate Cd4 transcription, whereas long and/or strong TCR signals terminate Cd8 transcription. MHC class I-restricted and MHC class II-restricted TCR signals are proposed to differ in both duration and intensity. Nat Rev Immunol,2008 Vol 8 No 11:788 7

8 T 细胞胸腺发育的转录因子 Complex regulatory requirements of T cell development at multiple T-lineage checkpoints. The figure summarizes genetic analyses showing functional dependence of T cell development on shifting combinations of multiple specific transcription factors, loss of any of which blocks at the indicated stages. Events occurring in the periphery are not included. For details, see text. Black, extreme dependence (knockout has severe effect). Gray, moderate or uncertain dependence. White, no dependence, possible antagonist effect. Broken lines indicate stages when factors are likely expressed but genetic evidence for functional dependence is lacking. Annu. Rev. Immunol :

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11 Treg, NKT 细胞来源于胸腺发育 Immunity 26, June

12 4. Immunological synapse 4.1 Junction formation 4.2 MHC-peptide transport 4.3 stabilization 12

13 Different molecular couples--the T cell receptor (TCR) and peptide- MHC, LFA-1 and ICAM-1, CD2 and CD48, CD28 and CD80--contribute to the formation of an immunological synapse between a T cell and an antigen presenting cell. 13

14 Chemokine induced cytoskeletal polarization. Nature Immunology 1, (2000) 14

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16 Model for actin dynamics in three stages of immunological synapse formation. Nature Immunology 1, (2000) 16

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18 Diversity of molecular-interaction zones of immunological synapse ( 稳定型突触 ) ( 分泌型突触 ) NATURE REVIEWS IMMUNOLOGY VOLUME 5 JULY

19 Diversity of molecular-interaction zones of immunological synapse ( 部分隔离型突触 ) ( 未隔离型突触 ) NATURE REVIEWS IMMUNOLOGY VOLUME 5 JULY

20 ( 动态型突触 ) NATURE REVIEWS IMMUNOLOGY VOLUME 5 JULY

21 Immunol Rev May;229(1): Dynamic process of Ag recognition and T-cell activation by T-cell receptor (TCR) CD28 microclusters and the immunological synapse 21

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23 5. General principles of transmembrane signaling 23

24 5.1 protein kinase Protein-tyrosine kinase,ptk: Src: p56lck, p59fyn (SH1,2,3:src-homologous domain ) Csk: p50csk Syk: ZAP-70 Jak: Jak1,2,3 Serine-threonine kinase: protein kinase C, PKC mitogen-activation protein kinase, MAPK phosphatylinositide 3 kinase, PI 3-K 24

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26 5.2 protein phosphatase Protein-tyrosine phosphatase, PTP, PTPase: CD45 Serine-threonine phosphatase: Calcineurin( 钙调磷酸酶 ) 26

27 5.3 ITAM and ITIM immunoreceptor tyrosine-based activation motifs immunoreceptor tyrosine-based inhibitory motifs 27

28 ITAM of T cell: D/EXX YXXL/V X(7-11)YXXL/V CD3 ITAM YXXL/V SH2 ITAM Lck, Fyn 28

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31 6. T cell signal transduction 6.1 Binding of antigen leads to clustering of antigen receptors on lymphocytes 6.2 Clustering of antigen receptors leads to activation of intracellular signals 6.3 intracellular signaling components recruited to activated receptors transmit the signal onwards from the membrane and amplify it 31

32 6.4 Small G proteins activate a protein kinase cascade that transmits the signal to the nucleus 6.5 Antigen receptor signaling is enhanced by co-receptors that bind the same ligand 6.6 Gene transcription and expression NF-AT, NF-κB, AP-1, CD28-rc, Stat 32

33 6.7 Cytokines signal lymphocytes by binding to cytokine receptors and triggering janus kinasea to phosphorylate and activate stat proteins 6.8 Programmed cell death of activated lymphocytes is triggered mainly through the receptor Fas 33

34 MHC II MHC II CD4 CD45 Early T cell activation 1 Receptor associated kinases accumulate under the membrane in close proximity to the cytoplasmic domains of the TcR -CD3 complex1 Fyn P 2 2 Lck As the T cell antigen receptor binds the MHC-peptide antigen, the phosphatase CD45 activates kinases2 such as Fyn,Lck This mechanism of activation is similar to the used to activate Syk in B cells Zap-70 34

35 CD4 CD45 MHC II T cell activation Fyn (or Lck) phosphorylates the ITAMs of CD3,, and ITAMS3 Fyn P 3 4 Lck The tyrosine kinase ZAP-704 binds to the phosphorylated ITAMs of CD3 - further activation requires ligation of the co-receptor, CD4 Zap-70 35

36 T cell activation MHC II Binding of CD4 co-receptor to MHC class II brings Lck into the complex, which then phosphorylates and activates ZAP-70 ZAP-70 phosphorylates LAT and SLP-765 Fyn P Zap-70 Lck 5 Activated ZAP-70 phosphorylates LAT & SLP-76 SLP-76 P P LAT P P Tyrosine rich cell membrane associated Linker of Activation in T cells (LAT) and SLP-76 associate with cholesterol-rich lipid rafts 36

37 MHC II T cell activation Activated ZAP-70 phosphorylates Guanine-nucleotide exchange factors (GEFS) that in turn activate the small GTP binding protein Ras Ras activates the MAP kinase cascade Fyn P Zap-70 Lck SLP-76 P P Tec Tec 6 LAT P P SLP76 binds Tec kinases6 and activates phospholipase C- (PLC- ) PLC- cleaves phosphotidylinositol bisphosphate (PIP 2 ) to yield diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) 37

38 3 4 1 Downstream of ZAP70 is adapter LAT(linker for Activation of T cell) and SLP-76 (SH2-Containing Leukocyte Phosphoprotein 76 kd) 2 PLCγ and Grb-2 Were recruited By LAT and SLP-76 38

39 CD45 发挥关键启动作用 A B C A B C Immunity 29, December 19, 2008;

40 Lck Lck acktivity 40 CD4 CD45 CD4 CD4

41 422 Immunity 27, September

42 ZAP70 发挥关键接头作用 42

43 CD28 发挥重要协同作用 43

44 Nat Rev Immunol VoL 8(9):701, 2008 T-cell receptor signalosome modules and their connections. 44

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46 TCR 信号的负调分子 46

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63 Abbreviations AHR, aryl hydrocarbon receptor; BATF, basic leucine zipper transcription factor, ATF-like; BCL-6, B cell lymphoma 6; BLIMP1, B lymphocyte-induced maturation protein 1; BTLA, B and T lymphocyte attenuator; CBL-B, Casitas B-lineage lymphoma B; CRTH2, chemoattractant receptorhomologous molecule expressed on TH2 cells; CTLA4, cytotoxic T lymphocyte antigen 4; CXCR, CXC-chemokine receptor; EOMES, eomesodermin; FOX,forkhead box; GATA3, GATA-binding protein 3; GITR, glucocorticoid-induced TNF-receptorrelated protein; GRAIL, gene related to anergy in lymphocytes; IκBζ, inhibitor of NF-κB-ζ; ICOS,inducible T cell co-stimulator; inos, inducible nitric oxide synthase; IRF4, interferon-regulatory factor 4; ITCH, itchy homologue E3 ubiquitin protein ligase; J, joining region; KGF, keratinocyte growth factor; LAG3, lymphocyte activation gene 3; LTα, lymphotoxin-α; MAF, musculoaponeurotic fibrosarcoma oncogene; MAIT, mucosal-associated invariant T; MBD2, methyl-cpg-binding domain protein 2; MR1, MHC-related protein 1; NEDD4,neuronal precursor cell-expressed developmentally downregulated 4; p27kip1, p27 kinase inhibitory protein 1; PD1, programmed cell death 1; PLZF, promyelocytic leukaemia zinc-finger; ROR, retinoic acid receptor-related orphan receptor; RUNX3,Runt-related transcription factor 3; SAP, SLAM-associated protein; SLAM, signalling lymphocytic activation molecule; SMAD, mothers against decapentaplegic homologue; STAT, signal transducer and activator of transcription; TFH, T follicular helper; THPOK, TH-inducing POZ/Kruppel-like factor; TIM3, T cell immunoglobulin domain and mucin domain protein 3; 63

64 Fuelling the T-cell response by Neil Smith, Nat Rew Immunol, November 2005 vol 5 no 11 64