Dev of T-cells Flashcards
Major site of T-cell dev
Thymus
-Occurs in ordered process via several CHECKPOINTS
What checkpoints?
- Gene rearrangements generate a multitude of TCR
- In thymus T-cells become MHC-restricted and lineage committed
- Selection occurs at several stages
- -Positive
- -Negative
What do each of us have?
A self-restricted TCR repertoire
–out T-cells recognize OWN self, but not necessarily others
MHC restriction primer
T-cells recognize peptides derived from self/foreign Ags ONLY when bound to self MHC molecules
MHC restriction?
T-cells recognize context - T-cell will recognize Ag only when bound to self MHC molecule
What MHC do CD4+ and CD8+ recognize?
CD4+ = MHC class 2 CD8+ = MHC class 1
What is the importance of thymus?
T-cell development
without it individuals are immunodeficient
Parts of thymus
Cortex - densely packed
Medulla - loosely packed
Cortical-medullary junction - separates cortex from medulla
How does T-cell move in thymus as developes
Cortex–>Medulla
What occurs to function of thymus as increase in age?
Function declines
What is the migration to and from thymus?
- T-cell precursors travel from BM to thymus for dev
- Mature T-cells leave thymus and travel to 2ndary lymphoid tissues
Immigration and Emigration
- T-cell precursors (prothymocytes) derived from fetal liver and BM seed in thymus
- Thymus produces chemotatic factors to attract T-cell progenitors
- Cells that seed the thymus enter the cortico-medullary junction, via blood vessels
- Thymocytes that survive rigorous selection leave thymus
What controls the migration process?
- Chemokines
2. Sphigosine 1-phosphate receptors
How is flow cytometry used to ID stages of TC dev?
By markers present on T-cell
What are the 2 major classes of T-cells?
**alpha-beta
gamma-delta
Lineage commitment
- All start as CD34+ uncommitted progenitor (DN)
- Then either go Alpha-Beta or Gamma-Delta based on gene rearrangement of beta,gamma,delta (uncommitted DP)
- If commits to beta, allows alpha chain to rearrange (committed)
How do lineage choices occur?
TCR gene rearrangements
- depends on which of B,G,D are rearranged
- ->If beta–>Alpha beta – PRE-TCR
- ->if G andD –> Gamma delta
How does pre-TCR know it works?
Pre-T-cell (mimics alpha chain) and interacts w/ beta chain to see if it workds
-if doesn’t - will undergo further rearrangement
If don’t succeed at working TCR what happens?
Two attempts can be made to achieve a productive rearrangement of the Beta chain
What if still not functional after rearrangement of Beta chain?
The alpha chain can sustain attempts at a functional rearrangement
What occurs as a result of alpha chain rearrangement?
Eliminates delta chain locus
–>Now can’t go back to gamma-delta unit
How do T-cells know self from non-self
Through + and - selection
Positive selection
DP thymocytes recognize MHC in epithelial cells and undergo further dev
-MHC class 1 –>CD8
-MHC class 2–> CD4
If cant recognize they die
Negative Selection
DP thymocytes bind to tightly to MHC and will die
Ligands for + and - selection
Are self-peptides/MHC complexes expressed on stromal and hematopoetic cells
How to prevent TCRs that would react with BM-derived cells in the periphery?
Presentation of self-peptides from hematopoetic cells play imp role in shaping the repertoire
What protect peripheral tissue specific Ags?
The AIRE transcription factor - plays role in regulating the expression of some tissue specific Ags in medullary epithelial cells in the thymus
What is the T-cell Repertoire?
The sum of all the specificities of the mature T-cells produced by the thymus
–>We all have diff MHCs so we will have diff T-cells
