Selection of T cell receptor repertoire and CD4/CD8 lineage commitment Flashcards
Where do T cells come from?
Originate in bone marrow and the multipotent lymphoid progenitors migrate to the thymus
In the thymus, they undergo further differentiation to become pre-T cells and are educated to differentiate self from non-self
The positively selected T cells then emigrate from the thymus to mediate and effect the cognate immune response
How do T the lymphoid progentiors migrate to the thymus?
Thymus secretes chemokines which are transported to the bone marrow, so T cells can recognise the chemokines follow their trail (conc gradient) back to thymus
Where are thymocytes at different developmental stages found in the thymus?
Label the 2 TCR complexes
TCR along with CD4 or CD8 should be seen as a TCR complex which can bind to either MHC class I or II
Summarise the T cell development and migration
Why do Gamma-delta T cell’s separate from the main path, and they undergo very little differentiation before exiting the thymus
Gamma-delta T-cells are favoured during early foetal development, then decrease in levels during adulthood
Gamm-delta T cells are not MHC restricted - the gamma-delta receptor does not recognise the MHC peptide
In some cases ligands for the gamma-delta TCR are self proteins which are upregulated under stress conditions
Play a role in cancer surveillance
What happens to the cells that fail to complete thymocyte maturation?
95% of them will undergo death by neglet = apoptosis
Macrophages will then ingest them and recycle some components
Requires Fas, which is present on the surface of a apoptotic cell, or one thought to be toxic - along with FasLigand (which ill bind to TNF in extrinsic apoptosis process)
Following this, a signalling pathway occurs leading to activation of Caspase enzymes which will eventually disintegrate DNA and kill the cell
What are the fates awaiting a double positive thymocyte?
Double positive cells have both CD4 and CD8 present on their surface
They will look for MHC molecules in the thymic tissue
- Completely random whether CD4 or CD8 will find MHC class 1 or 2 first and binds
- If that binding is strong enough, it will lead to down regulation of the other CD molecule, and so the cell will merge as a single positive CD (with no or little expression of the other CD which has been downregulated)
- If the binding is not strong enough, then the double positive cells will be killed by apoptosis or neglect and removed from the tissue
What is positive selection?
= Occurs when double positive TCR binds to MHC molecules (HLA Molecules) in thymus
If the binding is strong enough, the cell will be positively selected and will continue or will be allowed to continue to develop, compared to weak or no binding leading to apoptosis
What is negative selection?
Required to exclude the self-reactive T cells - as they would cause autoimmunity
The remaining T cells in the thymus have been selected on the basis that they can bind to HLA molecules so they could potentially become useful but there also needs to be regulation in a way so they don’t act on the host’s own tissues or cells or antigens = negative selection
What happens if self proteins are presented on the surface of a T cell?
Negative selection:
- If the binding is weak (between MHC and TCR) - that cell does not pose a danger it might turn against the host’s cells and will not trigger activation. Weak binding means T cell is positively selected and may go onto become a conventional T cell
- However if binding to a self-peptide is very strong, it creates a problem for the host and can mean the T-cell could become self-reactive and could cause autoimmunity and turn against the hosts own tissues and cells leading to apoptosis as it is too dangerous to keep
A proportion of the cells will lead to regulatory T cells
How are T cells negatively selected against self-antigens not present in the thymus?
AIRE (the transcription factor autoimmune regulator) mediates ectopic gene expression in the thymic medullary stroma
= promiscuous gene expression –> eliminates many self-reactive T cells
What happens to T cells that pass both positive and negative selection?
Become conventional T cells
They migrate to secondary lymphoid organs looking for their target antigen
If they encounter specific antigen, they get activated, proliferate and become effector T cells
- Some become memory T cells
If they don’t find a target, they will die by apoptosis after period of circulation
