chapter10

Kuby Immunology, Sixth Edition

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CHAPTER 10: T-CELL MATURATION, ACTIVATION, AND DIFFERENTIATION I. T-CELL MATURATION AND THE THYMUS A. T Cell Maturation (Review) T cells are self-MHC restricted Require successful rearrangement of TCR genes Signal through CD3 complex Coreceptors (CD4, CD8) interact with MHC, provide costimulatory signal Costimulatory molecules (B7, CD28) necessary for response Accessory molecules stabilize interaction and/or signal B. T Cell Development Progenitors originate in bone marrow Migrate to thymus during gestation → thymocytes (d11 mice, week 8-9 human) Mature, immunocompetent T cells exit to periphery GENERATES A T CELL REPERTOIRE THAT IS SELF-MHC RESTRICTED AND SELF-TOLERANT! 1
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CHAPTER 10: T-CELL MATURATION, ACTIVATION, AND DIFFERENTIATION C. T Cell Development in vitro D. Expression of T Cell Surface Markers T cell precursors (outer cortex): No TCR, RAG, or CD3 TCR genes rearranged No CD4 or CD8 = D ouble N egative (DN) CD4 CD8 DN1-4 (slow proliferation) identified by expression of the following: c-kit- receptor for stem cell growth factor CD44- adhesion molecule CD25- IL-2 receptor To proceed down αβ pathway, DN cells: Turn off c-kit, turn down CD44, turn on RAGs Rearrange β chain, pair with pre-Tα chain **No productive rearrange→apoptosis Complex with CD3 = pre-T Early studies limited to thymic organ cultures In 2002, T cell development induced by notch/notch ligand interaction Notch ko: NO T-cell maturation Notch forced expression in HSC – ALL T cells/ NO B cells Thus, notch is KEY protein in T lineage commitment 2
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CHAPTER 10: T-CELL MATURATION, ACTIVATION, AND DIFFERENTIATION E. Formation of the Pre-T Cell Receptor Indicates to cell that a productive β chain was made F. Thymic Development Signal through pre-TCR + CD3: Suppresses further β rearrangement Permissive for α rearrangement Expression of CD4 AND CD8 = D ouble P ositive (DP) CD4 + CD8 + DP cells begin to proliferate again: RAG-1 and RAG-2 made, but RAG-2 is rapidly degraded, no rearrangement of α chain Important for increasing TCR repertoire When proliferation stops: RAG-2 accumulates α chain rearranges in population of cells with successful β chain rearrangements (TCR) Can proceed to positive and negative selection 3
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CHAPTER 10: T-CELL MATURATION, ACTIVATION, AND DIFFERENTIATION G. Low Percentage of Thymocytes Reach Maturity ~98% of thymocytes die in thymus No productive rearrangement → apoptosis Fail to survive positive selection Survivors → immature SP CD4 + or CD8 + Does not recognize MHC → must die here! SP undergo additional negative
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chapter10 - CHAPTER 10: T-CELL MATURATION, ACTIVATION, AND...

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