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BIOL 2005 (40)

Cell Selection and Central Tolerance

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Carleton University
BIOL 2005
Elizabeth Nisbet

IMMUNOLOGY T CELL SELECTION AND CENTRAL TOLERANCE Tolerance-state of the immune system characterized by unresponsiveness to a particular antigen - ability to distinguish self from non self (unique and important to IS) FREEMARTIN condition in twin cattle: BURNET hypothesis -dizygotic twins sharing a placenta will therefore share RBC’s (hematopoitic chimera [share stem cells] -developing/immature lymphocytes are subject to CLONAL DELETION in presence if self-antigens are recognized CLONAL DELETION MODEL -self tolerance learned by developing immune system –occurs during fetal and neonatal development -tolerance decreases rapidly -if exposed to antigen in embryotolerance in adultrejection -If receptor of immature lymphocyte engages a self-antigendeletion of that clone T-CELLS – more important than B-cells for tolerance Central Tolerance – generated during lymphocyte development, involves clonal deletion Peripheral Tolerance – generated AFTER lymphocytes have matured involves ANERGY (inactivation) T CELL DEVELOPMENT (occurs in thymus in 3 stages) 1) TCR gene rearrangements resulting in productive α/β dimers on cell surface α/β have many more V/J segments than γ/δ δ is located within α(between J and V)  this prevents α/β and γ/δ co-expression -γ/δ actually occurs first (5% committed to distinct T cell lineage for innate immunity (double negative) 1. V/J rearrangements in α/β and γ/δ  usually α/β wins 2. β gene rearrangement completes first (double negative) -required to progress to double positive! (can induce SCID mouse with TCRβ transgene) -β pre TCR α complex associated with CD3 signals successful completion of TCRβ gene rearrangement -Without good TCRB cant place BpreTCRa or progress to the next phase -similar to μ-λ5-vpreB complex in developing B cells (λ5 is surrogate like pre TCRα) 3. CD4 and CD8 coexpression (but not in γ/δ) 4. if αgene rearrangement is successful  α/β TCR expressed on surface if unsuccessful  cell dies 2) CELLULAR SELECTION: Negative Selection – for self-reactive “thymocytes” Positive Selection – recognize foreign antigens in presence of SELF MHC 3) Acquisit
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