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Immunology > T cell Development > Flashcards

T cell Development Flashcards

1
Q

How many T cells are in 1ml of blood?

A 
1 e6 (1 milion) in blood
There is lymphocytes under skin and lining the gut
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2
Q

Where do T cells develop?

A

Thymus

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3
Q

What defines a T cell?

A

The presence of a T cell receptor.

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4
Q

Describe the pathway of development and differentiation in the thymus

A

Development: First stem cell is called CD4-8-
Later in development, the cell downregulates one of CD4/8.

Differeniation: In periphery antigen stimulates naive T cells to become effector cells to clear infection.
Effector cells die after resolution; some are memory cells.

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5
Q

What is he ratio of the different types of T cells?

A

2 CD4+: 1 CD8+

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6
Q

Describe the pathway of development and differentiation in the thymus

A

Development: First stem cell is called CD4-8-
Later in development, the cell downregulates one of CD4/8.

Differentiation: In periphery antigen stimulates naive T cells to become effector cells to clear infection.
Effector cells die after resolution; some are memory cells.

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7
Q

Where do T cells develop?

A

Thymus; this shrinks from heart-size to very small; more T cells needed early on.

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8
Q

What defines a T cell?

A

The presence of a T cell receptor.

It does not see bacteria or virus; it only sees processes pathogenic peptides via MHC that will cause a response. presentation.

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9
Q

In periphery, CD4+ have various roles

A

he differentiation determined by cytokines.

  • Regulatory T cells which control the immune system.
  • Th1, respond to Tb disease and makes IFN-gamma.
  • Th17, which makes IL17
  • Th2, mediates allergies making IL4.
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10
Q

What benefit to T cells does recognition of self peptides have?

A

All MHC molecules must have peptide; only way it can be on surface. Lot of different self peptides presentated

T cells recognise self peptide-MHC and this triggers T cell survival.

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11
Q

What are the two classes of T cell

A

This is determine by TRC-protein complex on surface

1) alpha/beta TCR due to the alpha/beta dimer to recognise the peptide. These are in blood and lymphatic circulation
2) gamma/delta TCR due to the gamma/delta dimer used for recognition. These are in gut, and skin.

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12
Q

gamma-delta T cells

A

Primary specific immune responses, monitoring tumours, wound healing.

These are not dependant on specialised antigen presenting cells for activation. Ligand unknown.

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13
Q

alpha/beta T cells

A

These recognise small peptides-MHC 1/2 and mainly mediate antigen-specific

Two types of alpha/beta cells: CD4+, CD8+

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14
Q

Briefly describe the function of CD4+ and CD8+ ?

A

CD4+: They produce cytokines and growthfactors to regulate other immune cells

CD8+: They differentiate to make cytotoxic cells that can kill virus infected cells

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15
Q

gamma-delta T cells

A

Primary specific immune responses, monitoring tumours, wound healing.

These are not dependant on specialised antigen presenting cells for activation. Ligand unknown.

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16
Q

What makes the TCR so variable?

A

alpha/beta subunits are highly varible; the other subunits which are responsible for signal transduction from membrane into cell are invariable

the genes encoding alpha/beta subunits undergo protein rearrangements which increases protein diversity

Each cell will have thousands of the same TCR molecule

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17
Q

alpha/beta T cells

A

Alpha and beta are disulphide linked heterdimer.

These recognize small peptides-MHC 1/2 and mainly mediate antigen-specific

Two types of alpha/beta cells: CD4+, CD8+

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18
Q

Describe the TCR gene beta loci

A

from right-left: There is variable regions, exons of diveristy regions, joining regions and constant regions

Recombinase genes called RAG1 and RAG2 randomly rearrange these exons during T cell development when the Beta subunit is forming to make V-D-J.

19
Q

What processes happen during V-D-J recombination?

A

The double stranded DNA is broken and DNA is cut out so certain exon regions can join.
DNA repair enzymes rejoin the free ends.

1) recombination from germline DNA to form rearranged DNA of joined V-J in alpha and V-D-J in beta chain.
2) Transcription and splicing translation leads to the final T cell receptor protein.

20
Q

What two selections are used to check all of the completely random gene rearragments

A

1) Positive selection: That it can recognise self peptides

2) Negative selection: that it does not have a high reactivity to self peptides.

21
Q

What is the diversity of V-D-J recombination

A

1 e18.

22
Q

Describe how to analyse a thymocyte? What is shown?

A

Pull thymus apart with needle, and stain the thymocytes with anti-CD4+ and anti-CD8+. Measure using a flow cytometer to get a fax-plot.

There are few double negative, but most cells double positive: 80%. These will differentiate into single positive.

23
Q

What controls the development of DP T cells into single positive cell?

A
  • antigen receptor
  • cytokines
  • cell itself

IL7 controls survival of DN cell stage. They then express the preTCR. If this is successful, the cell becomes double positive. If they express alpha/beta, it is this that determines which single positive cell.

24
Q

What is the preTCR composed of?

A

Beta chain, preT-alpha, and signalling subunits of CD3 antigen.

25
Q

Describe the T cell development and ALLELIC EXCLUSION

A

Enter Thymus:

1) rearrangement of ONLY ONE BETA TCR allele in cell precursor from bone marrow (DN)
2) If successfully rearranged BETA allele the thymocyte will express the pre-TCR
3) If this is expressed on the membrane it promotes cell survival and entry into the cell cycle. It downregulates RAG gene expression so the second beta gene is not rearranged.
4) Therefore only one beta chain, only one specificity
5) Cells with preTCR, proliferate and differentiate into cells that are DP
6) DP cells REXPRESS RAG genes which starts rearrangment of the alpha chain.

26
Q

What is allelic exclusion

A

Where only one allele is rearranged. (the second one may serve as a backup)

27
Q

What is the preTCR composed of? What is it function?

A

Beta chain, preT-alpha, and signalling subunits of CD3 antigen.

It induces:

  • survival
  • differentiation
  • proliferation
  • upregulation to SP

It does not need a ligand to signal, it simply expresses all subunits at the membrane in order to signal to next step and stabilize the complex.

28
Q

Describe the T cell development and ALLELIC EXCLUSION

A

Enter Thymus:

1) rearrangement of ONLY ONE BETA TCR allele in cell precursor from bone marrow (DN)
2) If successfully rearranged BETA allele the thymocyte will express the pre-TCR. If no B chain from either allele then cell will die.
3) If this is expressed on the membrane it promotes cell survival and entry into the cell cycle. It downregulates RAG gene expression so the second beta gene is not rearranged.
4) Therefore only one beta chain, only one specificity
5) Cells with preTCR, proliferate and differentiate into cells that are DP
6) DP cells REXPRESS RAG genes which starts rearrangment of the alpha chain.

29
Q

What is the preTCR composed of? What is it function?

A

Signaling complex: Beta chain, preT-alpha (invariant), and signalling subunits of CD3 antigen.

It induces:

  • survival
  • differentiation
  • proliferation
  • upregulation to SP

It does not need a ligand to signal, it simply expresses all subunits at the membrane in order to signal to next step and stabilize the complex.

30
Q

What two selections are used to check all of the completely random gene rearragments and that there is a useful TCR?

A

1) Positive selection: That it can recognise self peptides and MHC
2) Negative selection: that it does not have a high reactivity to self peptides and MHC; it becomes cross-reactive T cell and death signal triggered.

A moderate binding and presence of MHC triggers a survival signal.

It needs to recognise self but not strongly to cause autoimmunity.

31
Q

What is allelic exclusion?

A

Where only one allele is recombined. (the second allele may be used as a backup)

32
Q

What does ‘death by neglect’ refer to? When does the alpha chain recombine.

A

double positive cells express preTCR allowing the DP cell to survive as it is dimerised to the B chain. At this point (where cells are DP) the alpha chain is rearranged and simultaneous down regulation of the the preTCR.

If there is no successful alpha rearrangement by the time the preTRC is losT the cell will die; it has to replace dimer in time.

33
Q

What is the ligand in the thymus, which allow the TCR to signal

A

The self peptides

34
Q

Describe thymic epithelial cells and what is the significance of this?

A

They have unique patterns of expression which means it express lots of different protein not usually expressed by one cell.
This enables T cells to ‘see’ lots of different self peptide antigens from all around the body.

35
Q

What is AIRE and

A

Autoimmune disease where the gene AIRE has mutated. This gene contros the tissue specific antigens in thymus and so no AIRE means T cells are not selected for self-recognizing T cell.

T cells cannot be educated; need a new thymus.

Reacts with self insulin and destroys pancreas.

36
Q

The TCR

A

It regulates a cascade of signalling cascade that control T cell differentiation.

TCR cannot signal itself, (no intrinsic activity) but it can couple to intracellular tyrosine kinases such as Lck, Fyn and ZAP70 which are activated as the TCR is activated.

This coupling is through ITAM

37
Q

How does The TCR signal its activation?

A

It regulates a cascade of signalling cascade that control T cell differentiation.

TCR cannot signal itself, (no intrinsic activity) but it can couple to intracellular tyrosine kinases such as Lck, Fyn and ZAP70 which are activated as the TCR is activated.

Signals cause T cell to proliferate and become an effector cell..

This coupling is through ITAM

38
Q

What is ITAM

A

Immune tyrosine based Activation motif: an intracellular signalling motif

CD3 invariant subunits have 1 ITAM; dimer a/b has 3 ITAMs.

39
Q

What happens in terms of signalling if a ligand bind to TCR?

A
  • If ligand binds, co receptor (CD8+/CD4+) on T cell binds to ligand as well, stabilising complex.
  • ITAM become phosphorylated by kinase Lck.
  • ZAP70 (with a high affinity recognising domain for phosphorylating tyrosines) then binds to tyrosines of phosphorylated ITAMS of a/b dimer.
  • This means ZAP70 is activated and now phosphorylates proteins
40
Q

What is the function of ZAP70?

A

It phosphorylates adaptor proteins like:

  • LAT: which links activated T cells
  • SLP76
41
Q

What do ZAP70 phosphorylated adaptor proteins do?

A

They recruit SH2 domain containing enzymes to the membrane where the act to regulate the lipid metabolism.

LAT adaptor protein recruits regulatory proteins for RasGTPases for signalling pathways.

Cascade begins.

42
Q

Summary of TCR and signalling.

A

TCR is a signalling unit, it sees peptide-MHC it rapidly triggers biochemical changes inside the cell which indicate to the T cell to develop further into effector cells.

43
Q

What is used to measure how many phosphorylation occur inside the cell.

A

Mass spectrometer

Thousands of phosphorylations which change as soon as a ligand binds.

Overall causes changes in gene expression.

Immunology (19 decks)

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