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Chapter 12 T lymphocytes

Chapter 12 T lymphocytes. Introduction. T cell maturation in the thymus T cell receptor and T cell accessory molecules T cell subsets. Part I T cell maturation in the thymus. Differentiation course of T cells Selection of T cells in thymus---- positive selection and negative selection

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Chapter 12 T lymphocytes

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  1. Chapter 12T lymphocytes

  2. Introduction • T cell maturation in the thymus • T cell receptor and T cell accessory molecules • T cell subsets

  3. Part I T cell maturation in the thymus • Differentiation course of T cells • Selection of T cells in thymus---- positive selection and negative selection • TCR gene rearrangement during the maturation of T cells

  4. 1. Differentiation course of T cells1) pro T cells CD3- TCR- CD4- CD8-TCR β chain starts to rearrange DN2) pre T cellsCD3+ TCRpTα:β CD4+ CD8+3) immature T cells DP CD3+ TCR+ CD4+ CD8+the rearrangement of TCR α chain 4) mature T cells CD3+ TCR+ CD4+or CD3+ TCR+ CD8+SP TCR rearrangement Thymus selection

  5. Important events in the thymus • TCR rearrangement ----Functional TCR • Positive selection and Negative selection ----Mature T cell possessMHC restriction and self tolerance

  6. Pro-T cell pT: Pre-T cell Immature T cell Mature T cell

  7. 2. Selection of T cells in thymus • During the stage from DP (double positive) cells to SP (single positive) cells • Depend on the interaction of TCR and Ag peptide and MHC molecules

  8. Positive selection • If the TCRs of DP cells recognize and combine with Ag peptide---class I/II MHC molecules in an appropriate affinity, these DP cells will differentiate and develop continuously----SP • If the TCRs of DP cells can’t recognize Ag peptide---class I/II MHC molecules or recognize and combine with Ag peptide---class I/II MHC molecules in a high affinity,these DP cells will undergo apoptosis. • Acquire self MHC restriction • MHC molecules play important roles in positive selection: MHC-I------CD8+ expression MHC-II-----CD4+ expression

  9. Negative seletion • If the TCRs of SP Cells can’t recognize self antigen peptide-class I/II MHC molecules or combine with self peptide-MHC molecules in a low affinity, these SP cells will differentiate and develop continuously. • If the TCRs of SP Cells recognize and combine with self antigen peptide-class I/II MHC molecules in a high affinity, these SP cells will undergo apoptosis or become clonal anergy. • Acquired self tolerance • Self peptide play important roles in negative selection.

  10. 3. TCR gene rearrangement during the maturation of T cells (1) Gene structure of TCRαβ αchain (14 chromosome): V, J, C βchain (7 chromosome): V, D, J, C

  11. (14 chromosome) (7 chromosome)

  12. (2) Gene structure of TCRγδ γchain (7 chromosome): V, J, C δchain (14 chromosome): V, D, J, C

  13. (7 chromosome) (14 chromosome)

  14. (3) Characteristics of TCR gene rearrangement • More J gene segment • More N-nucleotides insert • More CDR3 diversity

  15. Part II T cell receptor and T cell accessory molecules • Antigen receptor complex ------recognizing antigen • Accessory membrane molecules ------Molecules related to the activation of T cells (co-receptors and co-stimulators) • Other surface membrane molecules

  16. I. Antigen receptor complex of T cells: TCR and TCR complex

  17. 1. TCR (1) Definition: A kind of membrane molecule on T cells that can specially bind to the antigenic peptide-MHC molecule complex. (2) Types： TCRαβ TCRγδ

  18. (3) Structure of TCR • Extracellular region: V region: V  and V  antigen binding site CDR1,CDR2,CDR3 C region: C and C • Transmembrane region: anchoring domain positive charged • Cytoplasmic region

  19. Three dimensional structure of TCR

  20.  TcR CD3 CD3              2. TCR complex (1) Definition: A group of membrane molecule on T cells that can specially bind to the antigen and pass an activation signal into cell, consisting of TCR ( or ) , CD3 (,, or ,, η)

  21. (2) CD3 • Consists of ,  , or ,, η • Important membrane molecule of T cells • Contain ITAM in the cytoplasmic region • Pass activatory signal into cells

  22. ITAM (Immunoreceptor tyrosine-based activation motif): ITAM is composed of 15-19 amino acid residues, and contains YxxL/Vx7-11YxxL/V consensus sequence. When TCR binds antigen specifically, the tyrosine in the consensus sequence will be phosphorylated by the receptor associated tyrosine kinases in order to transduct activatory signal.

  23. ITIM (Immunoreceptor tyrosine-based inhibition motif): ITIM contains I/VxYxxL consensus sequence and transducts inhibitory signal.

  24. II. Accessory membrane molecules on T cells 1. CD4 and CD8: co-receptor • CD4----MHC-II (β2) Receptor of HIV • CD8----MHC-I (α3) CD4 and CD8 also participate in signal transduction after TCR bind antigen specifically.

  25. Lck PTK Lck PTK TcR TcR CD8 CD4 3 2   MHC Class I MHC Class II CD4 and CD8 can increase the sensitivity of T cells to peptide antigen MHC complexes by ~100 fold T cell co-receptor molecules

  26. 2. Co-stimulatory receptor: CD28 • CD28 on silent or activatedT cells binds to the B7 (CD80/CD86)on APC ----transduct an important co-stimulatory signal to T cells • CTLA-4 (cytotoxic T lymphocyte antigen-4,CD152) on activated T cells binds to B7 on APC (The affinity is higher than that between CD28 and B7) ----transduct an inhibitory signal to T cells

  27. 3. CD2 (LFA-2, Sheep red blood cell receptor ) • CD2 is expressed on 90% mature T cells, thymus cell and NK cell, but there is no expression on B cells. • Its ligand is CD58 (LFA-3) expressed on APC, RBC of human or sheep……. • Functions: ------Mediated the formation of E-rossete. ------Enhance the binding of TCR and antigenic peptide-MHC molecule complex. ------Participate in signal transduction of T cell activation.

  28. 4. CD45 (leukocyte common antigen) • Act as protein tyrosine phosphatase • Express on mature and immature lymphocytes • Possess various isoenzyme (One is CD45R) CD45RA------ Naïve T cell CD45RO------ Effector and Memory T cell

  29. 5. CD40L (CD154) CD40L on T cell binds to CD40 on B cell or other APC ---Transduct a co-stimulatory signal to B cells ---Promote activation of B cells

  30. 6. LFA-1 ---Ligand: ICAM-1,2,3 ---Mediated adhesion between T cell and APC, vascular endothelial cells and extracelluar matrix

  31. III.Other surface membrane molecules 1. Mitogen receptor: ---Related to lymphocyte transformation test • PHA(植物血凝素), ConA(刀豆蛋白 A) ---Activating T cell only • PWM(美洲商陆) ---Activating T and B cells 2. Cytokine receptor: IL-1R, IL-2R 3. Class I and class II MHC molecules 4. L-selectin 5. CD44 6. VLA-4

  32. 参与 Th细胞活化的膜表面分子 Th细胞 APC CD4 TCR/CD3 MHC-II 1 LFA-1 ICAM-1 CD28 B7-1 2 CD28 B7-2 LFA-1 ICAM-3 LFA-1 ICAM-3 CD2 LFA-3 B7-1 CTLA-4 —

  33. Part III T cell subsets • According to activatory stage of T cells • According to type of TCR • According to expression of CD4 or CD8 • According to functions of T cell

  34. I. According to activatory stage of T cells • Naïve T cell • Effective T cell • Memory T cell

  35. Comparison of three types of cells Naïve T cell Effective T cell Memory T cell stimulation of Ag no yes yes IL-2R (high avidity) no yes yes CD45 CD45RA CD45RO CD45RO Lymphocyte yes no yes recirculation

  36. II. According to type of TCR αβ T cells γδT cells TCR diversity many few Distribution Peripheral blood 60-70% 5-15% Tissues lymph node,etc skin and mucosa Phenotype CD3CD2 100% 100% CD4+CD8- 60-65% <1% CD4-CD8+ 30-35% 20-50% CD4-CD8- <5% ≥ 50% Ag Peptide(8-17aa) lipid, HSP,etc MHC restriction yes no Functions Specific CMI non–specific CMI

  37. NKT cells: ---- αβ T cells existing in thymus, bone marrow, spleen and liver ----Express markers of NK cells (CD56 and NK1.1) ----Be lack of TCR diversity ----Recognize lipid antigen presented by class I MHC-like molecules (CD1d)

  38. III. According to expression of CD4 or CD8 CD4+ T cell CD8+ T cell Ag peptide exogenous endogenous 13-17aa 8-10aa MHC restriction Class II Class I Major effective Th Tc cells

  39. CD8+T cell(Tc) CD4+T cell(Th) T cell Receptor T cell Receptor Peptide Peptide CD4 CD8 MHC Class II MHC Class I Antigen Presenting Cell Antigen Presenting Cell

  40. IV. According to functions of T cell • Th cell (Th1,Th2,Th17) ----CD4+ • Tc cell or CTL----CD8+ • Regulatory T cell (Treg) ----CD4+CD25+Foxp3

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