Selection of T Cell Receptor Repertoire and CD4/CD8 Lineage Commitment Flashcards
How does the thymus allow for T cell progenitors to migrate into it (what does it do)?
Releases chemokines into the blood stream that reach the bone marrow so T cells will follow that back to the thymus.
What is the most frequent cells in the thymus?
Cortical/medullary epithelial cells (stromal cells)
What is Hassall’s corpuscle?
In the thymus medulla, is an aggregation of mature T lymphocytes (mostly T regulatory lymphocytes)
Which part of the thymus does late stage T cell development occur?
Medulla
What does CD stand for in T cell co-receptors?
Cluster of differentiation
Recap how flow cytometry can characterise T cell development
- Can show us if the cell is double negative, double positive or CD4 or CD8 positive
- Can also sub characterise double negative cells into DN1-DN4
How does the quantitiy of DN/DP/CD4/CD8 cells differ from the thymus in contrast to other organs such as the spleen?
- In the Thymus the most abundant type of T cell is the double negative (DN) but in other organs there will be very few DN and almost all cells will wither be CD4 or CD8
- as the selection to CD8 or CD4 happens in the thymus
Does T cell maturation and T cell receptor rearrangement occur sequentially or simulatenously?
Simultaneously
We know that T cells chose to be CD8 or CD4, but does a gamma delta T cell also need to make this choice??
The ‘normal’ T cell differentiation passage is for the alpha/beta T cells and the gamma/delta branch off before. Meaning that I think that gamma/delta do not express either CD4 or CD8
At what stage do γδ T cells branch off in the normal T cell development in the thymus?
Between DN2 and DN3
In which stage of human development are γδ more abundant than αβ?
During early foetal development
δγ T cells bearing specific receptors end up in the {?}, {?}, {?} and other places
δγ T cells bearing specific receptors end up in the skin, gut, uterus and other places
Describe the difference in the mechanism used to detect antigens by δγ T cells as opposed to conventional T cells
δγ T cells do NOT recognise peptides via MHC, but instead recognise them directly, similar to how an antibody would.
In some cases, ligands for δγ T cell TCRs are {?} that are upregulated under stress conditions
In some cases, ligands for δγ T cell TCRs are self proteins that are upregulated under stress conditions
In humans, circulating δγ cells recognise a {?(not peptide)} antigen in {?}. δγ cells also play a role in cancer surveillance.
In humans, circulating δγ cells recognise a phospholipid (not peptide) antigen in tuberculosis. δγ cells also play a role in cancer surveillance.
Roughly how many T cells are αβ instead of gamma/delta?
90% αβ
For a T cell to become a SP CD4+ cell, describe what the DP cell needs to progress to this stage
- Functional TCR alpha chain rearrangement
- CD4 and MHC II (to be a CD4+ cell)
- ERK singalling
- Calcineurin signalling
For a T cell to become a SP CD8+ cell, describe what the DP cell needs to progress to this stage
- Functional TCR alpha chain rearrangement
- CD8, MHC1 and TAP
- ERK signalling
- Calcineurin signalling
What signal (not PS) is expressed on a cell which induces apoptosis - in the context of death by neglect apoptosis of inadequate T cells
Fas binding to its ligand FasL
What is death by neglect?
I think this is just where if a T cell can not bind an MHC molecule (either 1 or 2) strongly enough then it can be killed either by apoptosis or by neglect (?)
Fully explain how T cells chose to become CD4 vs CD8 cells
DP positive cells look for MHC to bind to on epithelial cells or dendritic cells in the thymus
- if it finds MHC1 first and strong enough, it becomes a CD8 as it downregulates CD4
- if it binds to MHC2 first and strong enough, it becomes a CD4
This IS positive selection as if a T cell does not bind either then it dies (by neglect?)
What comes first postive or negative selection?
Positive then negative
What is positive vs negative selection?
Positive (first) is where we are testing to see if the T cell can bind strongly to MHC1 or MHC2 and if not it dies. This is also when it decides if it will be CD4/8. Allows only useful T cells to survive.
Negative selection is making sure that the T cell does not bind to self antigens
What HLAs are other names for MHC 1 and MHC2?
Both are on chromosome 6
- MHC1 = HLA-A, HLA-B, HLA-C
- MHC2 = HLA-DR, HLA-DQ, HLA-DP
Which cells of the thymic stroma are MHC 1 vs MHC 2 expressed?
MHC1 = thymic stromal cells and low levels on antigen presenting cells MHC2 = thymic medullary stromal cells and high levels on APCs
Explain fully the mechainsm of negative selection
Epithelial and dendritic (APC) cells will express any proteins within the cell (cytosolic, membrane…) on their surface
→ if a T cell binds weakly then the T cell is not dangerous, if it binds strongly then the T cell will apoptose
→ self reactive T cells have a second chance as they are not removed immediately and they undergo further rearragnement (to save on costs of making the cell)
In the thymus, not all self antiens are presented during negative selction, so how do we get around this problem?
Thymic cells allow expression of a specific transcription activator gene which increases transcription of other tissue-specific genes
- gene is called AIRE
What is the role of AIRE?
Allows for transcription of many tissue-specific genes in the medullary stroma of the thymus to allow for negative selection of more proteins including those not normally found within the thymus.
Summary of Positive and negative selection in the thymus
Some SP T cells stay in the thymus after selection and express high levels of {?} and {?}, these cells do not proliferate in response to MHC self-peptide complexes. These are {?} cells.
Some SP T cells stay in the thymus after selection and express high levels of CD25 and Foxp3, these cells do not proliferate in response to MHC self-peptide complexes. These are T regulatory cells.
T regs accumulate in {?} in the thymus
T regs accumulate in Hassall corpuscles in the thymus
Conventional T cells (cells that have passes both selections) migrate to {?} to look for their target antigen.
Conventional T cells (cells that have passes both selections) migrate to secondary lymphoid organs to look for their target antigen.
