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Chapter 13 Lymphocyte Maturation and Antigen Receptor Expression

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

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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

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