chpt 10
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- thymocytes
- developing t cells in the thymus; from them comes functionally distinct subpopulations of mature tcells
- positive selection
-
selects FOR tcells that have receptors capable of recognizing ONLY SELF MHC
Generates self-mhc restriction - Negative selection
- selects FOR cells that don't react too strongly with self MHC or self-MHC presenting self Ag.
- when pre-Tcells arive at thymus, do they have CD4, CD8, CD3 complex, or TCR?
- NO
-
what do Tcell precursors do when they get to the thymus?
what are these early cells called? -
enter outer/paracortex and proliferate.
DOUBLE-NEGATIVE CELLS - 2 alternative pathways for double-negative thymocytes to progress down:
-
gamma-delta; v. few do <5%
or Alpha-beta - most do. - WHAT makes Tcell population diverse?
-
-Junctional diversity (during rearrang)
-Random gene rearrangement - what percentage of thymocytes die in the thymus? what's the mechanism?
- 98%, by apoptosis
- what type of cells determine the haplotype of MHC that will restrict the Tcells for self-MHC-restriction?
- stromal cells in the THYMUS - where development occurs, positive selection
-
thymic stromal cells include:
their function is to: -
-epithelial cells
-macrophages
-dendritic cells
express both MHC class 1 and 2!! so interaction with immature thymocytes results in pos+ and neg- selection. -
+ selection ensures
- selection ensures -
MHC RESTRICTION
SELF TOLERANCE - generation of TCR diversity gives approx how many different Tcells?
- junctional variation and rearrangement give 10^15-18 differnt TCRs!
-
Where does:
Positive selection take place - thymic cortex
-
where does:
negative selection take place - thymic medulla
- what is produced by the first DNA rearrangement of Tcells
- cells go down alpha/beta or gamma/delta pathways.
- what happens to the gamma/delta population of Tcells after differentiation as thymocytes
- they increase and develop, then decline
- how do ++ cells become CD8+ or CD4+?
-
interact with MHC1 = CD8+
interact with MHC2 = CD4+ - remember how alpha chains of TCR wait to so that different ones can be expressed with the B chain? how does that help positive selection?
- because multiple a/B complexes, better chance that some will pass the test and bind self-MHC, thus not apoptose.
- 2 thymic selections; which takes place where?
-
positive - cortex - for selfmhc react.
negative - medulla - for self-peptide autoimmunity prevention. - what does the instruction model refer to
-
after maturation/gene rearrangement,etc, double positive cells become single CD4 or CD8.
Determining Factor: they are influenced by MHC1 or MHC2 - components of the cascade of signal transduction (triggered by ag/mhc/tcr binding)
-
-Tyrosine kinase
-Phosphorylase kinase
Calcium
Small G proteins - 2 signals for Th cell activation:
-
Signal one: peptide/mhc binds to Tcr
Signal two: CD28 binding to B7 on APC
(Co-stimulatory signal) - what 3 gene products are expressed after SIGNAL ONE in Th cell activation:
-
1. Transcription factors (turn other genes on)
2. Cytokine/Cytokine receptors (activate self and others)
3. Adhesion molecules (help TcR) - what binds to cytoplasmic domains of CD3 after signal one?
- tyrosine kinase; phosphorylates ITAM on intracellular domain. initiates signal cascade for Tcell activation!
-
Tcells recieve
only signal one: what happens?
both signals: what happens? -
1. Go into clonal anergic state
2. go into clonal expansion! - co-stim signal is active in WHO, when?
-
in professional APC (dendritic) ALL THE TIME; constitutive.
in Bcells and macrophages: only when ACTIVATED! - AICD: what is it, how its activated.
-
Activation Induced Cell Death;
When Tcell is activated, Fas is expressed and Fas-ligand binding stimulates apoptosis.
Glucocorticoids also stimulate it; treatments SHRINK thymus - Super Ag: exo or endotoxin?
- EXOTOXINS; lead to TSS, systemic shock.
- special note about gamma/delta TcR cells
- can bind Ag without MHC presentation; in skin epithelium. protect epithelial cells, remove dead cells