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Topics. Overview B cell development T cell development. Lymphocyte development overview. Ag receptors in B and T cells are immensely variable Diversity is generated during development by gene rearrangement Lymphopoiesis occurs mainly in Central Lymphoid Tissues (Bone Marrow & Thymus).

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  1. Topics • Overview • B cell development • T cell development BIOS 486A / 586A

  2. Lymphocyte development overview • Ag receptors in B and T cells are immensely variable • Diversity is generated during development by gene rearrangement • Lymphopoiesis occurs mainly in Central Lymphoid Tissues (Bone Marrow & Thymus) BIOS 486A / 586A

  3. Lymphocyte development overview (Cont) • Receptor diversity is produced by gene rearrangement and is random • Includes specificities that will bind to SELF • Lymphocytes go through a process of selection • Self-recognizing cells are removed from the system during development (Negative selection) • Sells that recognize self antigens weakly or that recognize self antigens in a particular way receive a survival signal (positive Selection) BIOS 486A / 586A

  4. Lymphocyte development overview (Cont) • Negative Selection ensures Immunological Tolerance • Positive Selection ensures MCH Restriction (T-cells) • Default fate = cell death • Most lymphocytes generated in the Bone Marrow do not survive • In the fetus lymphocytes are generated in the liver BIOS 486A / 586A

  5. In the fetus and juvenile individuals: • large production of new lymphocytes that populate the peripheral lymphoid tissues • In the mature individual: • New T cell production slows down. T cells are maintained by division of mature T cells. • New B cells are constantly being produced BIOS 486A / 586A

  6. BIOS 486A / 586A

  7. 4 stages of B cell development BIOS 486A / 586A Fig 6.1

  8. Development requires signals from to microenvironment to start gene rearrangements • Stromal cells (Stroma = mattress) • Specific adhesion contacts via interaction of cell-adhesion molecules and their ligands • Provide growth factors that stimulate lymphocyte differentiation and proliferation BIOS 486A / 586A

  9. B cell early development in the Bone Marrow BIOS 486A / 586A

  10. Development occurs in stages • is measured by successful rearrangement of genes and expression of receptor molecules • Development is accompanied by expression of other cell surface and intracellular proteins BIOS 486A / 586A

  11. BIOS 486A / 586A

  12. Productive rearrangement leads to protein expression • Non-productive rearrangement leas to apoptosis BIOS 486A / 586A

  13. B cell development in Secondary lymphoid organs • Immature cells complete development in secondary lymphoid organs • Spleen, Lymph nodes, MALT • Small proportion complete maturation and survive to recirculate between Lymphoid organs and the blood • Survival is a consequence of competition for a place in the pool of long-lived recirculating B cells • Follicular dendritic cells, located in FOLLICLES provide survival signals to all cells • B cells stay for one day in follicle BIOS 486A / 586A

  14. Immature B cells (Bone Marrow) Binding to Ag presented by cells? (multivalent) NO YES Apoptosis Binding to soluble Ag? NO YES Anergy Enter the secondary lymphoid tissue? YES NO Short life Mature B cells (Secondary Lymphoid tissues) B cell selection BIOS 486A / 586A

  15. T cell Development BIOS 486A / 586A

  16. T cell origin Fetus : Bone Marrow & Liver Infants, juveniles: Bone Marrow & Thymus – High production Adults: Thymus atrophied – #s maintained by division of Mature T cells BIOS 486A / 586A

  17. Thymic stroma BIOS 486A / 586A

  18. BIOS 486A / 586A

  19. B cell precursor T cell precursor B cell : : Th 1 Th 2 CD4 T helper cells CD8 Cytotoxic T cells Lymphid precursor BIOS 486A / 586A

  20. Progenitor cells enter thymus Differentiate into • Dendritic cells • : • : Double negative cells CD3- CD4- CD8- • chain gene rearrangement Double positive cells CD3+ CD4+ CD8+  chain gene rearrangement Single positive cells CD3+ Either CD4+ orCD8+ T cell development Fig 7.3 Cortex Medulla 7.8 BIOS 486A / 586A

  21. MHC restriction (a) (a) T cell (a) Y X X MHCa MHCb MHCa (a) Antigen presenting cell (b) (a) Fig 5.16 BIOS 486A / 586A

  22. Co-stimulation / Adhesion Molecules BIOS 486A / 586A

  23. CD3+ CD4 +CD8+ CD3+ CD4 +CD8+ CD3+ CD4 +CD8+ CD3+ CD4 +CD8+ CD3+ CD4 +CD8+ Thymic APC YES NO Rescue Ensures MHC restriction Death in 3 or 4 days Positive Selection of T cells Good interaction between TCR – MHC? BIOS 486A / 586A

  24. CD3+ CD4 +CD8+ Thymic APC Very strong interaction between TCR – MHC? YES NO CD3+ CD4 + CD3+ CD4 + CD3+ CD4 + CD3+ CD4 + CD3+ CD8+ CD3+ CD8+ CD3+ CD8+ CD3+ CD8+ Apoptosis Negative Selection of T cells BIOS 486A / 586A

  25. BIOS 486A / 586A Fig 7.23 4th Ed

  26. T cells monitor APC If interaction, T cells proliferate and differentiate If no interaction, T cells leave Cell – Cell interactions in the Lymph Node T cells enter lymph node Fig 8.2 BIOS 486A / 586A

  27. BIOS 486A / 586A

  28. BIOS 486A / 586A

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