Germinal Center Response

1. Germinal Center Response

2. Hypermutation and selection • Affinity of Serum Ig increases during an immune response • Somatic mutation in Ig V region genes, in response to protein, in B cells in mouse spleen does not start until after the onset of Ab production • 2. Mutational process occurs in centroblasts--> centrocytes are selected on basis of their capacity for activation by antigen held on FDCs

3. The Germinal Center Reaction B cells being tested for antibody affinity Light zone Antigen-retaining FDCs Macrophage capturing dead B cells Dark zone Rapidly dividing and mutating B cells deep in the center

4. Memory cell plasmablast +CD40L Apical light zone plasmablast Interaction w/Ag. ? Basal light zone Outer zone No interact. W/Ag. Death by apoptosis ? Dark zone

8. Migration of plasma cells

9. Immunological Memory Four distinct phases 1. Induction of B cell memory GC reaction 2. Maintenance of a B cell memory compartment Non-secreting precursor to the memory response 3. Expression of B cell memory on re-challenge 4. Replenishment of the memory compartment

10. Summary of B-cell Development in Periphery

11. Major Events of Development and Maturation for T- and B-cells Are Similar

12. T-cell Development Occurs In the Thymus While B-cell Development Is in Bone Marrow

13. Thymic Stroma Provides A Unique Microenvironment for T-cell Development Thymic Stroma: A network of epithelia cells; Analogous to the bone marrow stromal cells that are required for B-cell development.

14. Experimental Data Demonstrating the Critical Role of the Thymic Stroma in T-cell Development Scid (severe combined Immunodeficiency) mice: defect in antigen-receptor gene rearrangement; Nude (hairless) mice: defect in whn transcription factor required for the differentiation of epithelial cells including thymic epithelial cells

15. Naïve T-cell Stem cell CD44+ CD25- Bone marrow Periphery Thymus Major Stages of T-cell Development CD4-8-

16. Figure 7-13 Cell Surface Markers of T-cell Development

17. Process Gene Rearrangement Cell Rearrangement of TCR Genes Is an important indicator of T cell development

19. Double Positive Positive Selection Negative Selection Single Positive High avidity recognition of peptide-MHC Failure to recognize peptide-MHC Positive selection serves to generate a self-MHC-restricted T-cell repertoire, and negative selection is to eliminate developing T cells whose antigen receptors bind self antigens with high avidity Selections and T-cell Maturation

20. Co-receptor Specificity of T-cell Is Determined by the Types of MHC that the TCR interacts with

21. Positive Selection Is Mediated by Thymic Cortical Epithelial Cells

22. While the Positive Selection Is Mediated by Thymic Cortical Epithelia Cells, the Negative Selection Is Largely Mediated by Bone Marrow-derived APCs Via positive and negative selections, mature T cells acquire the ability to generate effector mechanisms that serve to eliminate foreign but not self antigens. Thus, peptidesbound to MHC determine final T-cell receptor repertoire.

23. Experimental Data Showing That the Difference Between Positive and Negative Selection Is Due to the Different Avidity of TCR Signaling High Avidity Negative selection Low Avidity Avidity of interaction between TCR/peptide-MHC is to denote the strength of signal received by a T-cell, reflecting the affinity of TCR for its ligand,the number of ligands that bind at the same time, and the contribution of CD4 or CD8. Positive selection No interation

24. Bim Too strong signaling from TCR p53 … Bak/Bax Bcl-2 MITOCHONDRIA Apoptosome Cytochrome c Apaf-1 Smac IAP caspase 3 caspase 9 CELL DEATH Bim Plays an Important Role in Negative Selection of Lymphocytes

25. The ligation of TCR Cross-link of the receptors PLCg activation Ras & Rac activation DAG generation IP3 generation MAP kinase cascade PKC activation Ca2+ release Canonical NF-kB NFAT AP-1 Gene expression(IL-2, etc) Signaling via TCR Is Required for T-cell Maturation and Survival

26. The Traffic of Lymphocytes Is Controlled by Chemokines

27. Summary of T-cell Development in Thymus

28. Summary of T-cell Development in Periphery

29. Outline of T-cell Development and Maturation Abbas

30. The / Lineage is Distinct from the / Lineage

33. Experiment showing education of T cells by Thymic Epithelium

36. Humoral Immune Response

38. Figure 9-1 part 2 of 2

39. Two types of antigen, thymus-dependent (T-dependent) and thymus-independent (T- independent)

40. Thymus dependent antigen:Antibody response requires 2nd signal from T cellMHC class II/peptide-TCR activates T cells --> expression of CD40L on T cell. CD40L interaction with CD40 on the B cell is the second signal

41. The same CD4+ T cells (Thelper TH) that recognize peptide-MHC class II, stimulate the B cells that recognize the same Ag through The BCR

42. Thymus independent antigen:Can get second signal from TOLL receptor or cytokine signaling. Usually the antigen is polymeric

45. Activation of TH cell by MHC class II peptide induces Expression of CD40L and cytokines, that activate B cells

46. Meeting of antigen-binding B and T cells at the border Between the T-cell and B cell zones in the spleen

47. Production of a germinal center

48. Lymphocytes circulate continually from the blood into the peripheral Lymphoid tissues, they enter by squeezing between the specialized endothelial cells that appear to be larger than those found elsewhere in the body-->High Endothelial venules (HEV).