Late Stages of T cell Development in the Thymus Flashcards
Where do T cells come from?
- Multipotent lymphoid progenitors migrate from the bone marrow to the thymus
- In the thymus, the lymphoid progenitors differentiate to pre-T cells and are educated to differentiate self from non-self
- Positively selected T cells emigrate from the thymus to mediate and affect the cognate immune response
How do T cells migrate from the bone marrow to the thymus?
The thymus will produce small chemicals called chemokines such as thymosin, which are secreted and transported in the blood all the way to the bone marrow where T cell progenitors will recognise these signals and follow the chemokines all the way to the thymus
What zones in the thymus contribute to different T cell development stages?
The medulla is where the late stages of T cell development occurs
In the cortex we can see cortical epithelial cells and in the medulla medullary epithelial cells
Lymphocytes are spread throughout the thymus
Dendritic cells and macrophages as well in the medulla
Hassall’s corpuscle is where aggregation of mature lymphocytes occurs at the end
Thymocytes at different developmental stages are found in distinct parts of the thymus
The DN thymocytes interact with cortical epithelial cells to become DP thymocytes
Finally there is generation of a single positive T lymphocyte either CD4 or 8
What happens to gamma-delta T cells?
Gamma delta T cells diverge from the pathway and undergo very little further differentiation before exiting the thymus
gd T cells are favoured during early foetal development
They then subside progressively until they will represent only a small proportion in adults
How are gamma-delta thymocytes different from alpha-beta?
Antigen recognition by gd T cells is different than ab T cells
gd T cells bearing specific receptors end up in skin (Vg5), gut (Vg2), uterus (Vg6), etc.
gd T cells are not MHC restricted!
Antigen is recognized directly, more like an antibody would recognise an antigen
In some cases ligands for the gd TCR are self proteins upregulated under stress conditions
In humans, circulating gd cells recognize a phospholipid antigen from Mycobacterium tuberculosis
Play a role in cancer surveillance
What does a DP thymocyte need to progress to the SP stage?
- Functional TCRa 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 are inadequate T cells apoptosed?
It acquires this particular interaction between a molecule called Fas, present on the surface of to-be-apoptotic cells and Fas ligand (FasL) expressed on other cell types
The interaction activates a signalling pathway ending up with expression of caspase enzymes which will cleave or disintegrate DNA and therefore kill the cell
How are DP thymocytes get selected to be SP?
DP thymocytes will look for MHC molecules in the thymic tissue
The MHC molecules may be present on the epithelial cells or on APCs in the thymus
It is completely random as to whether a CD4 or CD8 will first find an MHC either I or II on the other cell
Which ever find the target first will bind to that MHC and if that binding is strong enough it will result in down regulation of the other CD
If the binding is not strong enough these DP thymocytes are killed by death by neglect (apoptosis)
What are the different types of HLA?
In humans MHC is HLA specifically HLA-A, C and B are class I- expressed on thymic stromal cells and in low levels on APC HLA-DR, DQ and DP are class II- expressed on thymic medullary stromal cells and high level on APCs
How are thymocytes positively selected for?
Occurs when DP T cells bind to MHC/HLA molecules and if the binding is strong enough is positively selected and becomes SP for either CD4 or 8
Positive selection ensures that only T cells are that are useful and can engage in recognition are selected
DP CD4/CD8 cells bind to MHC-I or MHC-II on thymic epithelial cells – it is a random event which one binds
Following adequate binding of CD4:MHC-II, CD8 is downregulated and vice versa
From here on, the SP CD4 or CD8 T cells are ready for negative selection
Unselected cells die by apoptosis
What is the reason T cells are negatively selected for?
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
Self-reactive cells are not removed immediately but go through further TCR rearrangements (second chance) – before they are eventually removed if still self-reactive
A bit of a problem for T cells: 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)
This gene is called AIRE (Autoimmune Regulator): this allows negative selection against most bodily self-proteins
How are T cells negatively selected for?
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
This eliminates many self-reactive T cells
What are Treg cells like?
High expression of CD25 and Foxp3
Do not proliferate in response to MHC self-peptide complexes
T Regs accumulate in Hassall corpuscles and later migrate to different tissues
Main role: dampen T cell response
What happens after T cells pass the selection process?
T cells that pass both positive and negative selection become conventional T cells
They migrate to secondary lymphoid organs looking for their target antigen
‘Immunological synapse’
If they encounter specific antigen, they get activated, proliferate and become effector T cells
Some become memory T cells
If they don’t find the target they, eventually die by apoptosis after period of circulation
How are TCR chains diverse?
TCR chains undergo V(D)J recombination to generate diversity; they also exhibit allelic exclusion
- TCRb chain is selected with an invariant pTa chain at the DN3 stage - TCRa chain is selected with pre-existing TCRb chain at the DP stage
