L16 - T-Cell Development: Receptor Repertoire Selection & CD4/CD8 Lineage Commitment Flashcards
How do T-cells migrate from the bone marrow to the Thymus?
The Thymus releases chemokines like Thymosin, Thymotaxin, Thymopoetin, and Thymic factors.
These travel through the blood vessels, and T-cells in the bone marrow recognise the chemokines and leave bone marrow.
They enter into the blood vessels and migrate to the thymus
What parts of the Thymus so thymocytes mature through?
At the edge into the middle:
Subcaspular region
Cortex
Cortico-medullary Junction
Medulla
What does CD in CD4/8/3 stand for?
Cluster of Differentiation
Describe the change in favoured T-cells throughout development?
Gamma-delta Thymocytes are favoured during early foetal development and the levels decrease into adulthood.
Alpha-beta Thymocytes are expressed less in foetal development and increase throughout adulthood
Describe how Antigen recognition by gamma-delta T-cells is different to alpha-beta cells?
Gamma-delta T-cells are not MHC restricted, the antigen is recognised directly, more like an antibody
In some cases, ligands for gamma-delta TCR are self proteins upregulated under stress conditions
Play a role in cancer surveillance.
What key factors are needed for DP T-cells to progress to the SP stage?
- Functional TCR chain rearrangement
- CD4 and MHC II (To be a CD4+ cell)
- CD8, MHC I and TAP (To be a CD8+ cell)
- ERK signaling
- Calcineurin signaling
How does a DP T-cell become a SP T-cell?
Which ever MHC molecule the DP T-cell encounters first, (either MHC Class 1 or class 2), will cuase the downregulation of the other CD molecule.
eg: if a CD8 finds class 1 MHC first it will become SP CD8+ T-cell
if a CD4 finds class 2 MHC first it will become SP CD4+ T-cell
What happens to T-cells that dont find MHC?
Death by neglect
Negative Selection
State the process of exclusion of Self-reactive T-cells?
Negative T-cells
Describe the process of Negative Selection?
If T-cell binding to MHC is relatively weak, then it does not pose a threat to the host, as it wont attack on the self
cells. It becomes conventional T-cells
However, if the T-cell binds strongly, there is a chance it may turn against the host cell, and so it is redirected for apoptosis.
Describe the purpose of Negative Selection?
Negative selection ensures that self-reactive cells are removed, as they would cause autoimmunity
This is determined based on affinity of TCR for presented
self-peptide: high – kill him, low – keep him
This ensures that remaining T cells are only reactive to
foreign peptides
Describe one limitation of negative selection and its solution?
Thymus does not represent
all self-antigens
but it has a transcription activator gene which can induce expression of other tissue specific proteins (kidney, heart etc).
What is AIRE?
Autoimmune Regulator - this allows negative selection against most bodily self-proteins
It is a transcription activator gene which can induce expression of other tissue specific proteins (kidney, heart etc)
What is ‘Promiscuous Gene Expression’?
The Transcription Factor Autoimmune Regulator (AIRE)
Mediates Ectopic Gene Expression in the Thymic Medullary
Stroma – other tissue specific genes…kidney, heart, liver,
lungs, gut, … apart from brain and testes
• This is known as promiscuous gene expression – about 10% of
all genes in thymus are expressed this way
What do regulatory T-cells express high levels of?
CD25 and Foxp3
