Selection of T Cell Receptor Repertoire and CD4/CD8 Lineage Commitment Flashcards

1
Q

How does the thymus allow for T cell progenitors to migrate into it (what does it do)?

A

Releases chemokines into the blood stream that reach the bone marrow so T cells will follow that back to the thymus.

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2
Q

What is the most frequent cells in the thymus?

A

Cortical/medullary epithelial cells (stromal cells)

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3
Q

What is Hassall’s corpuscle?

A

In the thymus medulla, is an aggregation of mature T lymphocytes (mostly T regulatory lymphocytes)

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4
Q

Which part of the thymus does late stage T cell development occur?

A

Medulla

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5
Q

What does CD stand for in T cell co-receptors?

A

Cluster of differentiation

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6
Q

Recap how flow cytometry can characterise T cell development

A
  • 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
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7
Q

How does the quantitiy of DN/DP/CD4/CD8 cells differ from the thymus in contrast to other organs such as the spleen?

A
  • 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
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8
Q

Does T cell maturation and T cell receptor rearrangement occur sequentially or simulatenously?

A

Simultaneously

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9
Q

We know that T cells chose to be CD8 or CD4, but does a gamma delta T cell also need to make this choice??

A

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

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10
Q

At what stage do γδ T cells branch off in the normal T cell development in the thymus?

A

Between DN2 and DN3

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11
Q

In which stage of human development are γδ more abundant than αβ?

A

During early foetal development

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12
Q

δγ T cells bearing specific receptors end up in the {?}, {?}, {?} and other places

A

δγ T cells bearing specific receptors end up in the skin, gut, uterus and other places

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13
Q

Describe the difference in the mechanism used to detect antigens by δγ T cells as opposed to conventional T cells

A

δγ T cells do NOT recognise peptides via MHC, but instead recognise them directly, similar to how an antibody would.

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14
Q

In some cases, ligands for δγ T cell TCRs are {?} that are upregulated under stress conditions

A

In some cases, ligands for δγ T cell TCRs are self proteins that are upregulated under stress conditions

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15
Q

In humans, circulating δγ cells recognise a {?(not peptide)} antigen in {?}. δγ cells also play a role in cancer surveillance.

A

In humans, circulating δγ cells recognise a phospholipid (not peptide) antigen in tuberculosis. δγ cells also play a role in cancer surveillance.

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16
Q

Roughly how many T cells are αβ instead of gamma/delta?

A

90% αβ

17
Q

For a T cell to become a SP CD4+ cell, describe what the DP cell needs to progress to this stage

A
  • Functional TCR alpha chain rearrangement
  • CD4 and MHC II (to be a CD4+ cell)
  • ERK singalling
  • Calcineurin signalling
18
Q

For a T cell to become a SP CD8+ cell, describe what the DP cell needs to progress to this stage

A
  • Functional TCR alpha chain rearrangement
  • CD8, MHC1 and TAP
  • ERK signalling
  • Calcineurin signalling
19
Q

What signal (not PS) is expressed on a cell which induces apoptosis - in the context of death by neglect apoptosis of inadequate T cells

A

Fas binding to its ligand FasL

20
Q

What is death by neglect?

A

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 (?)

21
Q

Fully explain how T cells chose to become CD4 vs CD8 cells

A

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?)

22
Q

What comes first postive or negative selection?

A

Positive then negative

23
Q

What is positive vs negative selection?

A

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

24
Q

What HLAs are other names for MHC 1 and MHC2?

A

Both are on chromosome 6

  • MHC1 = HLA-A, HLA-B, HLA-C
  • MHC2 = HLA-DR, HLA-DQ, HLA-DP
25
Q

Which cells of the thymic stroma are MHC 1 vs MHC 2 expressed?

A
MHC1 = thymic stromal cells and low levels on antigen presenting cells
MHC2 = thymic medullary stromal cells and high levels on APCs
26
Q

Explain fully the mechainsm of negative selection

A

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)

27
Q

In the thymus, not all self antiens are presented during negative selction, so how do we get around this problem?

A

Thymic cells allow expression of a specific transcription activator gene which increases transcription of other tissue-specific genes
- gene is called AIRE

28
Q

What is the role of AIRE?

A

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.

29
Q

Summary of Positive and negative selection in the thymus

A
30
Q

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.

A

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.

31
Q

T regs accumulate in {?} in the thymus

A

T regs accumulate in Hassall corpuscles in the thymus

32
Q

Conventional T cells (cells that have passes both selections) migrate to {?} to look for their target antigen.

A

Conventional T cells (cells that have passes both selections) migrate to secondary lymphoid organs to look for their target antigen.