Overview B cell development T cell development
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1 Topics Overview B cell development T cell development 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) 2/1/2005 BIOS 486A / 586A 1 2/1/2005 BIOS 486A / 586A 3 Lymphocyte development overview Lymphocyte development overview (Cont) 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) 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 2/1/2005 BIOS 486A / 586A 2 2/1/2005 BIOS 486A / 586A 4 1
2 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 2/1/2005 BIOS 486A / 586A 5 2/1/ stages BIOS of 486A B / 586A cell development 7 Fig 6.1 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 2/1/2005 BIOS 486A / 586A 6 2/1/2005 BIOS 486A / 586A 8 2
3 B cell early development in the Bone Marrow 2/1/2005 BIOS 486A / 586A 9 2/1/2005 BIOS 486A / 586A 11 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 Productive rearrangement leads to protein expression Non-productive rearrangement leas to apoptosis 2/1/2005 BIOS 486A / 586A 10 2/1/2005 BIOS 486A / 586A 12 3
4 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 T cell Development 2/1/2005 BIOS 486A / 586A 13 2/1/2005 BIOS 486A / 586A 15 B cell selection Immature B cells (Bone Marrow) T cell origin 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) 2/1/2005 BIOS 486A / 586A 14 Fetus : Bone Marrow & Liver Infants, juveniles: Bone Marrow & Thymus High production Adults: Thymus atrophied #s maintained by division of Mature T cells 2/1/2005 BIOS 486A / 586A 16 4
5 Thymic stroma Lymphid precursor B cell precursor T cell precursor B cell α:β γ:δ Th 1 Th 2 CD4 T helper cells CD8 Cytotoxic T cells 2/1/2005 BIOS 486A / 586A 17 2/1/2005 BIOS 486A / 586A 19 T cell development Fig 7.3 Progenitor cells enter thymus Differentiate into Dendritic cells γ:δ α:β Cortex Medulla Double negative cells CD3 - CD4 - CD8 - β chain gene rearrangement Double positive cells α chain gene rearrangement 2/1/2005 BIOS 486A / 586A 18 Single positive cells Either or CD8 2/1/ BIOS 486A / 586A 20 5
6 MHC restriction Positive Selection of T cells T cell Thymic APC X X Y MHC a MHC b MHC a Antigen presenting cell Fig /1/2005 BIOS 486A / 586A 21 (b) YES CD4 Rescue + CD8 + Ensures MHC restriction Good interaction between TCR MHC? NO Death in 3 or 4 days 2/1/2005 BIOS 486A / 586A 23 Co-stimulation / Adhesion Molecules Negative Selection of T cells Thymic APC Very strong interaction between TCR MHC? YES NO 2/1/2005 BIOS 486A / 586A 22 CD8 + Apoptosis CD8 + 2/1/2005 BIOS 486A / 586A CD CD8 + 6
7 2/1/2005 BIOS 486A / 586A 25 Fig th Ed 2/1/2005 BIOS 486A / 586A 27 Cell Cell interactions in the Lymph Node T cells enter lymph node T cells monitor APC Fig 8.2 If no interaction, T cells leave If interaction, T cells proliferate and differentiate 2/1/2005 BIOS 486A / 586A 26 2/1/2005 BIOS 486A / 586A 28 7
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