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Topics
• Overview• B cell development• T cell development
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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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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)
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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
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• 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
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4 stages of B cell development
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• 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
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B cell early development in the Bone Marrow
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• 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
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• Productive rearrangement leads to protein expression
• Non-productive rearrangement leas to apoptosis
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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
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B cell selectionImmature B cells (Bone Marrow)
Mature B cells(Secondary Lymphoid tissues)
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
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T cell Development
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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
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Thymic stroma
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Lymphid precursor
B cell precursor
B cellα:β γ:δ
CD8Cytotoxic T cells
CD4T helper cells
T cell precursor
Th 1
Th 2
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T cell developmentProgenitor cells enter thymus
Differentiate into •Dendritic cells•γ:δ•α:β
Double negative cellsCD3- CD4- CD8-
Double positive cellsCD3+ CD4+ CD8+
β chain generearrangement
α chain generearrangement
Single positive cellsCD3+
Either CD4+ oror CD8+
Fig 7.3
Cortex
Medulla
7.8
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MHC restriction
T cell
Antigen presenting cell
MHCa MHCb MHCa
X X Y
Fig 5.16
(a) (a)(a)
(a) (a)(b)
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Co-stimulation / Adhesion Molecules
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Positive Selection of T cells
CD3+
CD4 +CD8+
ThymicAPC
Good interaction betweenTCR – MHC?
CD3+
CD4 +CD8+ CD3+
CD4 +CD8+
CD3+
CD4 +CD8+CD3+
CD4 +CD8+ RescueEnsures MHC restriction
YES
Death in 3 or 4 days
NO
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CD3+
CD4 +CD8+
Very strong interaction betweenTCR – MHC?
Negative Selection of T cells
ThymicAPC
YES
Apoptosis
NO
CD3+
CD4 +CD3+
CD4 +
CD3+
CD4 +
CD3+
CD4 +CD3+
CD8+
CD3+
CD8+
CD3+
CD8+
CD3+
CD8+
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Fig 7.23 4th Ed
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Cell – Cell interactions in the Lymph NodeT cells enter lymph node T cells monitor APC
If interaction, T cells proliferateand differentiate
If no interaction, T cells leave
Fig 8.2
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