医学免疫学英文教学课件：Chapter12 T lymphocytes

1、1Chapter12 T lymphocytes3ContentsPart T cell maturation in the thymusPart T cell receptor and T cell accessory molecules Part T cell subsets 45Thymic microenviromentDifferentiation course of T cellsSelection of T cells in thymus- positive selection and negative selectionPart T cells maturation in th

2、e thymus61. Thymic microenvironment782. Differentiation course of T cells 1) Pro T cells CD3- TCR- CD4- CD8- TCR chain starts to rearrange DN2) Pre T cellsCD3+ TCRpT: CD4+ CD8+ 3) Immature T cells DP CD3+ TCR+ CD4+ CD8+ the rearrangement of TCR chain 4) Mature T cells CD3+ TCR+ CD4+ or CD3+ TCR+ CD8

3、+ SPTCR rearrangementThymus selection9CD3CD4+ CD8 TCR CD3CD4CD8- TCR CD3LOWCD4CD8-TCRabLOW CD3+ CD4+ CD8+ TCRab+ CD3+ CD4+ CD8 TCRab+ CD3+ CD4 CD8+ TCRab+ CD3+ CD4+ TCRab+ CD3+ CD8+ TCRab+ CD3+ CD4+ CD8+ TCRgd+ CD3+ CD4+ CD8 TCRgd+ CD3+ CD4 CD8+ TCRgd+ CD3+ CD4 CD8 TCRgd+ CD3+ CD4 CD8 TCRgd+ CD3+ TC

4、Rgd+ CD3CD4/LOW CD8 TCRCD3CD4/LOW CD8 TCRCapsule Subcapsular region CortexBone marrow Medulla Thymus lobules10Differentiation of T cells in thymusChanges in thymus：TCR rearrangement -functional TCRPositive selection and negative selection T cells acquire MHC restriction and Self tolerance11123. Sele

5、ction of T cells in thymusDepend on TCR, MHC and Ag peptide TCRMHC: positive selection TCR-self antigen peptide: negative selectionDuring the course from DP(double positive) cells to SP(single positive) cells13Positive selection DP cells whose TCRs recognize and combine with MHC molecules can differ

6、entiate and develop continuously-SP DP cells whose TCRs cant recognize with MHC molecules or bind with high affinity go apoptosis Get self MHC restrictionMHC molecules play an important role in positive selection: MHC-CD8+ expression MHC-CD4+ expression1415MHC-ICD8 on DP cellsCD4 decreaseCD4-CD8+ T

7、cellMHC-II CD4 on DP cellsCD8 decreaseCD4+CD8- T cell16DP cellCD8+SP cell17DP cellCD4+SP cell18Negative seletionCells whose TCRs cant recognize with self antigen peptide develop and differentiate continuously.SP cells whose TCRs recognize and combine with self antigen peptide tightly go apoptosis or

8、 become clonal anergy.Acquire self tolerance1920212223Part TCR and T cell accessory moleculesAntigen receptor complex-recognizing antigenAccessory molecules-related to the activation(CDw90)24 TCR and TCR complex251. TCR(1)Definition: A kind of membrane molecules on T cells that can specifically reco

9、gnize and bind to the antigenic peptide-MHC molecule complex.(2)Types：TCR TCR26(3) Structure of TCRExtracellular region: V region: V and V antigen binding site CDR1,CDR2,CDR3 C region: C and CTransmembrane region: Cytoplasmic region: +27Three dimensional structure of TCR28 CDR1CDR3CDR229(3) Structur

10、e of TCRExtracellular region: V region: V and V antigen binding site CDR1,CDR2,CDR3 C region: C and CTransmembrane region: anchoring domain positive charge Cytoplasmic region: cant transmit signal （312aa）+302. TCR complex(1)Definition: A group of membrane molecules on T cells that can specifically b

11、ind to the antigen and transmit activation signal into T cells, consisting of TCR ( or ), CD3(, ).TCRCD3CD331(2) CD3Consists of , .Important membrane molecules of T cells Transmit activation signal into T cells Contain ITAM in the cytoplasmic region 32 ITAM (Immunoreceptor tyrosine-based activation

12、motif):ITAM is a conserved motif composed of two copies of the sequence tyrosine-X-X-leucine found in the cytoplasmic tails of various membrane proteins that are involved in signal transduction. When these receptors bind their ligand, the tyrosine residues of the ITAMs will be phosphorylated by the

13、receptor associated tyrosine kinases in order to transmit activation signal.CD3, Ig, Ig, some activating receptors333435 ITIM (Immunoreceptor tyrosine-based inhibition motif):ITIM contains I/VxYxxL consensus sequence and transmits inhibitory signal. 36T cell accessory moleculesAccessory molecules-re

14、lated to the activation 3738391. CD4 and CD8: co-receptorCD4-class MHC（2） Receptor of HIVCD8-class MHC (3 ) CD4 and CD8 also participate in signal transduction after TCR bind antigen specifically.D1D2D3D4Lck40CD4+T cell414243CD4+T cell (Th)CD8+T cell (Tc)T cellReceptorPeptideMHCClass IIT cellRecepto

15、rPeptideMHCClass IAntigen PresentingCellAntigen PresentingCellCD4CD8442. Co-stimulatory receptor: CD28 CD28 on resting or activated T cells binds to the B7(CD80/CD86) on APC Contain ITAM domainTransmit an important co-stimulatory signal to T cells45CTLA-4CD40L463. CTLA-4CTLA-4(cytotoxic T lymphocyte

16、 antigen-4, CD152) on activated T cells binds to B7 on APC Homologous to CD28Bind to B7 with high affinityContain ITIM domainTransmit an inhibitory signal to T cells47484. CD2 (LFA-2, Sheep red blood cell receptor)Expressed on 90% mature T cells (none on B cells)Its ligand is CD58(LFA-3) expressed o

17、n APC, RBC of human or sheepFunctions: -Mediate the formation of E-rossete -Enhance the binding of TCR and antigenic peptide-MHC molecule complex -Participate in signal transduction of T cell activation495. LFA-1(lymphocyte function antigen-1)CD11a/CD18 (2 integrin subfamily)Its ligand is ICAM-1(CD5

18、4),2,3Mediate adhesion between T cell and APC or target cell6. VLA-4(very late antigen-4)CD49d/CD29 (1 integrin subfamily)Its ligand is VCAM-1,fibronectin,lamininMediate adhesion between T cell and target cell507. Mitogen receptor: -Related to lymphocyte transformation testPHA(phytohaemagglutinin,植物

19、血凝素), ConA(ConcanavalinA,刀豆蛋白 A) -Activating T cell onlyPWM(Droopraceme Pokeweed,美洲商陆) -Activating T and B cells 8. Cytokine receptor: IL-2R,IL-12R519. Other accessory moleculesCD45 -CD45RA: naive T cell -CD45RO: effector T cell, memory T cellL-selectin: GlyCAM-1,CD34CD4452According to activating st

20、age of T cellsAccording to type of TCRAccording to expression of CD4 or CD8According to functions of T cell Part T cell subsets 531. According to activating stage of T cellsNave T cell (CD45RA, L-selectin)Activated T cellEffector T cell (CD45RO, CD44, VLA-1)Memory T cell (CD45RO, CD44, VLA-1)54 Nave T cell Memory T cellStimulation of Ag no yesIL-2R(high avidity) no yesCD45 CD45RA CD45RO MHC- molecule no yes ICAM no yes552. According to type of TCR56 3. According to expression of CD4/CD8CD4+ T cellCD8+ T cell574. According to functions of T