BLG 307 Lecture Notes - Apoptosis, Thymocyte, Clonal Deletion

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28 Jan 2013
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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 embryotolerance in adultrejection
-If receptor of immature lymphocyte engages a self-antigendeletion 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 α gene 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) Acquisition of mature effector function
either CD4 or CD8 is inactivated
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