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Chapter 13 Lymphocyte Maturation and Antigen Receptor Expression PowerPoint Presentation
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Chapter 13 Lymphocyte Maturation and Antigen Receptor Expression

Chapter 13 Lymphocyte Maturation and Antigen Receptor Expression

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Chapter 13 Lymphocyte Maturation and Antigen Receptor Expression

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  1. Chapter 13Lymphocyte Maturation and Antigen Receptor Expression

  2. Contents Chapter 13Lymphocyte Maturation and Antigen Receptor Expression • PartⅠ Introduction of hematopoietic stem cell • PartⅡ T cell maturation and B cell maturation • PartⅢ BCR diversity and TCR diversity

  3. PartⅠ Hematopoietic stem cell • Pluripotent hematopoietic stem cell--bone marrow • Marker: CD34, CD117(c-kit) • Myeloid progenitor + lymphoid progenitor • Myeloid progenitor EPO, TPO, CSF, IL • Lymphoid progenitor NK, DC, T, B • NK marker: CD56+CD16+ • T cell: TCR, CD3, CD4/CD8, CD28, CD2, LFA-1 • B cell: BCR, IgαIgβ, CD19/CD21/CD81,CD40 B7, MHC, CKR

  4. PartⅡ T cells maturation and B cells maturation • Development and differentiation of T cells • Development and differentiation of B cells

  5. SectionⅠ Differentiation of T cells in thymus • Thymic microenviroment • Differentiation course of T cells • Selection of T cells in thymus---- positive selection and negative selection

  6. 1. Thymic microenvironment

  7. 2. 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

  8. Bone marrow CD3‾CD4‾/LOW CD8‾ TCR‾ Thymus lobules Capsule CD3‾CD4‾/LOW CD8‾ TCR‾ Subcapsular region CD3+ CD4+ CD8+ TCRgd+ CD3‾CD4+ CD8‾ TCR‾ CD3‾CD4‾CD8- TCR‾ CD3+ CD4+ CD8‾ TCRgd+ CD3LOWCD4‾CD8-TCRabLOW Cortex CD3+ CD4‾ CD8+ TCRgd+ CD3+ CD4+ CD8+ TCRab+ CD3+ CD4‾ CD8‾ TCRgd+ CD3+ CD4‾ CD8‾ TCRgd+ CD3+ CD4+ CD8‾ TCRab+ CD3+ CD4‾ CD8+ TCRab+ Medulla CD3+ TCRgd+ CD3+ CD4+ TCRab+ CD3+ CD8+ TCRab+

  9. Differentiation of T cells in thymus Changes in thymus: • TCR rearrangement ----functional TCR • Positive selection and negative selection T cells acquireMHC restriction and Self tolerance

  10. 3. Selection of T cells in thymus • Depend on TCR , MHC and Ag peptide TCR—MHC: positive selection TCR---self antigen peptide : negative selection • During the course from DP(double positive) cells to SP(single positive) cells

  11. Positive selection • DP cells whose TCRs recognize and combine with MHC molecules can differentiate and develop continuously----SP • DP cells whose TCRs can’t recognize with MHC molecules or bind with high affinity go apoptosis • Get self MHC restriction • MHC molecules play an important role in positive selection: MHC-Ⅰ------CD8+ expression MHC-Ⅱ------CD4+ expression

  12. Negative seletion • cells whose TCRs can’t recognize with self antigen peptide develop and differentiate continuously • SP cells whose TCRs recognize and combine with self antigen peptide tightly go apoptosis or become clonalanergy • Acquired self tolerance

  13. SectionⅡ Development and differentiation of B cells • Differentiation of B cells in Bone marrow • Differentiation of B cells in peripheral lymphoid tissue

  14. μ

  15. Differentiation of B cells in Bone marrow----Ag independent • Hematopoietic stem cells • Lymphoid progenitor • Pro-B cells( chain rearrangement) • Pre-B cell( chain+ surrogate light chain ) • Immature B(mIgM,  chain +κchain orλchain) • Mature B(mIgM, mIgD) • Functional B repertoire

  16. Negative selection of B cells inbone marrow

  17. 2. Differentiation of B cells in peripheral lymphoid tissue----Ag dependant • Virgin B/naïve B cell most die • Plasma cell Ab • Memory B cell secondary immune response

  18. 3.Events in the differentiation of B cells:Gene rearrangement of IgNegative selectionImmature B cells : mIgM--self antigen mIgM -- self antigen apoptosis or anergy surviving to develop mature B cells

  19. Questions? • Why can TCR or BCR recognize so many Ag in nature? • Why does IgM produce earlier than others? • How does Ig produce BCR and Ab? • How can B produce different type of Igs? • ---------------?

  20. PartⅢ BCR diversity and TCR diversity • BCR diversity • TCR diversity

  21. SectionⅠ BCR diversity • Gene structure of Ig • Gene rearrangement of Ig • Characteristics of Ig gene expression • Mechanism of Ig diversity

  22. 1. Gene structure of Ig (human) H chain:14 chromosomeV region encoding genes:VH (variable gene segments) – 65 DH (diversity gene segments) – 27 JH (joining gene segments) – 6 Leader sequence—signal peptide C region encoding genes:CH (constant gene segments): Cμ, Cδ, Cγ et al.(11)

  23. L chain(--2 chromosome, --22 chromosome)V region encoding genes: --V, J–40, 5 -- V, J–30, 4Leader sequence—signal peptideC region encoding genes:C (1); C(4)

  24. In heavy chains, the V, D and J segments encode the variable domain while the C segment encodes the constant domain. In light chains, the V and J segments encode the variable domain while the C segment encodes the constant domain.

  25. (a)  Chain (22 chromosome)) V JC JC JC JC (2 chromosome)

  26. 2. Gene rearrangement of IgV-D-J rearrangement of H chain pro-B cells: D-J V-DJ VDJ DNA pre-B cells: VDJCμ VDJ- Cμ RNAmRNA V-J rearrangement of L chainpre-B cells: V  -J  V  J  DNA immature B cells: V  J CV  J  -CRNAmRNA transcription splicing

  27. C C C3 C 1 C1 C2 C4 C C2 C C C3 C1 C1 C2 C4 C C2 C C C3 C1 C1 C2 C4 C C2 C C C C 

  28. The expression of BCRIntranuclear:DNA rearrangement ------- V region encoding gene (VDJ or VJ) Transcription and splicing -------leader sequence + V region encoding gene + C region encoding gene (L gene-V gene –C gene)Extranuclear:translation -------- nascent peptide L-V-CEndoplasmic reticulum:assembly--------H chain and L chain (IgM or IgD)transportation------BCR (membrane Ig, mIg)

  29. 3. Characteristics of Ig gene expression ① recombination enzyme: RAG(recombination activating gene) TdT(terminal deoxynucleotidyl transferase) other DNA enzymes

  30. ② Allelic exclusion and isotype exclusionAllelic exclusion:only one of the two alleles in homologous chromosomes can be expressed. Isotype exclusion:only one of the two types of light chain genes can be expressed(:=65:35).

  31. Kuby Figure 5-10 Read Kuby pages 115-117: Allelic Exclusion Ensures a Single Antigenic Specificity

  32. ③ Isotype switching ( class switching ) Ag activated B cells proliferate VDJ is switched to recombine with another C region encoding gene IgM IgD, IgG, IgA, IgESwitching region

  33. CD4 T cells cytokines cytokines Thymus dependent antigen APC

  34. ④ Membrane type (BCR) and Secretory type Ig (Ab)

  35. 4. Mechanism of Ig diversity ① Combinatorial diversity human Ig: 65VH×27DH ×6JH=10530V 40V ×5J =200V 30V ×4J  =120V