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I. T cell maturation in the thymus 1. Process 2. Events

T cells I. T cell maturation in the thymus II. T cell receptor and T cell accessory molecules III. T cell subsets. I. T cell maturation in the thymus 1. Process 2. Events.

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I. T cell maturation in the thymus 1. Process 2. Events

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  1. T cellsI. T cell maturation in the thymusII. T cell receptor and T cell accessory moleculesIII. T cell subsets

  2. I. T cell maturation in the thymus1. Process2. Events

  3. 1.Process1) pro T cells CD3- TCR- CD4- CD8-TCR β chain starts to rearrange DN2) pre T cellsCD3+ TCRpTα:β CD4+ CD8+3) immature T cellsDP CD3+ TCR+ CD4+ CD8+the rearrangement of TCR α chain 4) mature T cells CD3+ TCR+ CD4+or CD3+ TCR+ CD8+SP

  4. Pre-TCR Vpre-T？ TCR b Pre-Ta g e e d Lck，ZAP-70，Syk 信号转导

  5. 2.events1) rearrangement of TCR gene2) positive selection and negative selection

  6. Rearrangement of TCR gene(1) germline gene structure of TCR(2) rearrangement of TCR genes(3) characteristics of the rearrangement of TCR genes(4) The mechanism of diversity of TCR

  7. (1) Germ-line Gene structure of TCRαβ αchain(14 chromosome): V, J, C βchain(7 chromosome): V, D, J, C

  8. (2) Gene rearrangement of TCRαβ αchain: VJ VJ-C VJC DNA RNA mRNA β chain: DJ VDJ VDJ-C VDJC DNA RNA mRNA

  9. (3) Characteristics of the rearrangment of TCR genesallelic exclusion

  10. (4) The mechanism of diversity of TCR1). Mutiple germline gene segments2). Combinatorial V(D)J joining3). Junctional flexibilityimprecise joining and N-nucleotides addition4). combinatorial assocination of α andβ chain

  11. Comparison of BCR and TCR functional genes • NO. of chain Chromosome V D J C • ----------------------------------------------------------------------- • BCR H 14 48 23 6 10 •  2 40 0 5 1 •  22 30 0 4 4 • TCR  14 50-100 0 100 1 •  7 20 2 14 2 •  7 7 0 4 4 •  14 5 2 6 1 • -------------------------------------------------------------------------

  12. 2) positive selection and negative selectionMHC restriction self tolerance

  13. 骨髓 CD3‾CD4‾/LOW CD8‾ TCR‾ 胸腺小叶 被膜 CD3‾CD4‾/LOW CD8‾ TCR‾ 被膜下区 CD3+ CD4+ CD8+ TCRgd+ CD3‾CD4+ CD8‾ TCR‾ CD3‾CD4‾CD8+ TCR‾ CD3+ CD4+ CD8‾ TCRgd+ CD3LOWCD4‾CD8+ TCRabLOW 皮质 CD3+ CD4‾ CD8+ TCRgd+ CD3+ CD4+ CD8+ TCRab+ CD3+ CD4‾ CD8‾ TCRgd+ CD3+ CD4‾ CD8‾ TCRgd+ CD3+ CD4+ CD8‾ TCRab+ CD3+ CD4‾ CD8+ TCRab+ 髓质 CD3+ TCRgd+ CD3+ CD4+ TCRab+ CD3+ CD8+ TCRab+

  14. Positive selection • DP cells whose TCR can recognize and combine with peptide-MHC molecule complexes expressed on the cortical epithelial cells in an appropriate affinity differentiate continuously to become SP cells. • DP cells whose TCR can’t combine with pepetide-MHC molecule complexes or can combine with them in a high affinity go apoptosis • Get MHC restriction • MHC molecules play important role in positive selection: MHC-I-------CD8+ expression MHC-II------CD4+ expression

  15. Negative seletion • SP cells whose TCR can’t combine with peptide-MHC complexes expressed on the DC or macrophages tightly develop and differentiate continuously • SP cells whose TCR recognize and combine with self antigen peptide –MHC complexes tightly go apoptosis • Acquired the self tolerance

  16. II. T cell receptor and T cell accessory molecules • T cell receptor complex • T cell accessory molecules

  17. TCR complex, Co –receptor, Co-stimulator receptor, immunological synapse

  18. 1.TCR cell receptor complex: a group of membrane molecules on T cells that can specially bind to the antigen and pass an activation signal into the cells, consisting of TCR (,) and CD3(, ,  or η)

  19. TCR: a kind of membrane molecule on T cells that can specially bind to the antigen (Recognize specifically with Ag-MHC complex) αβTCR External segment ------V region, C region Transmembrane segment Cytoplasmic segment γδTCR

  20. CD3:consisting of ,,  or η contain ITAMs, pass signal into cells ITAM: immune receptor tyrosine-based activation motif-----transduce activation signals from TCR

  21. α：阿尔法 Alpha β：贝塔 Beta γ：伽玛 Gamma δ：德尔塔 Delte ε：艾普西龙 Epsilon ζ ：捷塔 Zeta η：依塔 Eta

  22. 2. T cell accessory molecules (1) co-receptors ---CD4 and CD8 (2)costimulatory molecule receptors ----CD28, CTLA-4 (3) CD40L (4) CD45 (5) CD2 (6) mitogen receptor (7) Cytokine receptor

  23. co-receptors CD4 and CD8 CD4—MHC-II （β2） CD8----MHC-I (α3) Assist to recognize antigens Promote the activation of T cells

  24. Promote the signal transduction

  25. CD28 bind to the B7(CD80/CD86) on APC (antigen-presenting cell)----transduce a co-stimulatory signal to T cellCTLA4(cytotoxic T lymphocyte antigen-4, CD152) bind to B7 on APC ---transduce a inhibitory signal to T cellITIM

  26. CD40L CD40L --- CD40 on B cell ---transduce a co-stimulatory signal to B cells CD45 A cell surface glycoprotein with a cytoplasmic tyrosine phosphatase domain, is believed to play a role in T cell activation.

  27. CD2(erythrocyte receptor) ----E-rosette test CD2---IFA-3(CD58): promote the cells contact each other. LFA-1 lymphocyte function associate antigen –1:its ligand is ICAM (intercellular adhesion molecule).

  28. Mitogen receptor PHA(phytohemagglutinin), ConA(concanavalin A) ------activating T cell only PWM(pokeweed mitogen) -----activating T and B cells lymphocyte transformation test Cytokine receptor IL-1R, IL-2R etc.

  29. III. Subsets of T cellsaccording to activationnaive T cells, effective T cells and memory T cellsaccording to TCR T and  Taccording to CD4/CD8CD8+ Tcells, CD4+ Tcellsaccording to fuctionsTh, Tc/CTL and Treg

  30. naive T cell and memory T cell Ag naive T cell-----activated T cell---------- effective T cell and memory T cell naïve T cell memory T cell stimulation of Ag no yes IL-2R no yes CD45 CD45RA CD45RO MHC-II no yes ICAM no yes

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