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Flashcards in T cell activation Deck (40):
1

Generally describe the T cell immune resonse

1) naive T cells are activated via dendritic cells MHC-pathogen antigen and TCR.
2) rapid clonal expansion, proliferation and differentiation cause the specific TCR on effector T cells. Lymph nodes expand
3) apoptosis of T cells
4) Memory T cells aquired with specific TCR.

2

Describe the large cell contact between TCR/T cell and APC

There are lots of receptors in this interaction causing lots of signalling via tyrosine kinases.
-TCR: triggers interaction
-CD4+/CD8+
-integrins: cell adhesin
-co-stimultors

3

Describe the T cell response to activation

1) Changes migration patter in order to move to the site of infection
2) proliferate and clonally expand
3) Induce expression of genes for cytokines, cytokine receptors
4) Upregulate growth and protein synthesis so there is rapid cell division and cytokine making.
5) Differentiate into killer or helper so there is the correct immune response.

4

What is transmigration? Describe T cell migration in body.

circulating T cells receptors allow for transmigrate to secondary lymphoid tissue (spleen, lymph nodes) through the blood vessel wall.

Here T cells can find pathogen presented. If there is activation, they differentiate but then exit tissue to site of infection

If no activation, T cell goes to Lymphatic fluid where the are drained back into the blood.

Repeats

5

Describe the T cell response to activation caused by the TCR.

1) Changes migration patter in order to move to the site of infection
2) proliferate and clonally expand
3) Induce expression of genes for cytokines, cytokine receptors
4) Upregulate growth and protein synthesis so there is rapid cell division and cytokine making.
5) Differentiate into killer or helper so there is the correct immune response.

6

Describe the T cell response to activation caused by the TCR.

1) Changes migration patter in order to move to the site of infection
2) proliferate and clonally expand (Effector cells are larger, granular)
3) Induce expression of genes for cytokines, cytokine receptors
4) Upregulate growth and protein synthesis so there is rapid cell division and cytokine making.
5) Differentiate into killer or helper so there is the correct immune response.

7

What is Transcriptional reprogramming?

Number of Gene expressed changes after TCR activation up and down regulated

8

List some genes that are regulated by activation of T cells; transcriptional reprogramming

-Cytokine gene (IFN-gamma, IL2, TNF-alpha)

-Cytokine receptor gene

-Cell cycle regulator gene

-Nutrient transporter genes (amino acid, glucose, transferin) so T cells can match their metabolism to what is needed

-Chemokine receptors and adhesion molecules

9

What is the difference between the metabolism of naive unactivated T cells and effector cells (Cytotoxic)?

Naive:
Uses oxidative phosphorylation to make ATP. (These cells have low rates of glucose uptake, so it has to be efficient in producing glucose)

Cytotoxic:
High number of glucose and aa transporters.

The make alot of effector cytokines and protein synthesis which needs alot of ATP.
Become Glycolytic= They switch on aerobic glycolysis where they have excess to oxygen but use glycolysis instead

Using Glycolytic pathway, glucose can be broken down into lots of intermediates for RNA/DNA synthesis used in proliferation of the T cells.

10

What is the difference between the metabolism of naive unactivated T cells and effector cells (Cytotoxic)?

Naive:
Uses oxidative phosphorylation to make ATP. (These cells have low rates of glucose uptake, so it has to be efficient in producing glucose)

Cytotoxic:
High number of glucose and aa transporters.

The make alot of effector cytokines and protein synthesis which needs alot of ATP.
Become Glycolytic= They switch on aerobic glycolysis where they have excess to oxygen but use glycolysis instead

Using Glycolytic pathway, glucose can be broken down into lots of intermediates for RNA/DNA synthesis used in proliferation of the T cells.

11

What is the difference between the motility of naive unactivated T cells and effector cells (Cytotoxic)?

Naive:
They express chemokine receptor CCR7 and adhesion molecule CD62L.
This allows recirculation constantly blood.

Effector:
Downregulates CCR7/ CD62L and switch on expression of chemokine receptor CxCr3.
Stops cells migrating to lymphoid tissue and instead redirects them to peripheral tissues to mediate effector function.

12

What is the difference between the inflammatory cytokines of naive unactivated T cells and effector cells (Cytotoxic)?

Naive: IL7 receptor (from epithelial cells in lymph/bone) which enables cells to survive in lymphoid/bone.

Effector:
downregulates IL7 receptor and switches on inflammatory cytokine receptors IL2, IL12 which

13

What is the difference between the inflammatory cytokines of naive unactivated T cells and effector cells (Cytotoxic)?

Naive: IL7 receptor (from epithelial cells in lymph/bone) which enables cells to survive in lymphoid/bone.

Effector:
downregulates IL7 receptor and switches on inflammatory cytokine receptors IL2, IL12 which are sensitive to the cytokines from APC cell.

14

How does the activated T cell make a cytokine?

The expression of cytokine genes is regulated by combinations of different transcription factors.

15

How does the activated T cell make a cytokine?

The expression of cytokine genes is regulated by combinations of different transcription factors.

Non activated T cells: NFAT transcription factor is sitting in cytosol phosphorylated. No expression of genes

TCR activated, TF gets dephosphorylated and travels to nucleus.

It forms partnerships with other TF in nucleus. The complex binds to promoters of cytokine genes and causes IL2 production.

16

What is NFAT?

A transcription factor called Nuclear Factor of Activated T cells.

There are 5 NFAT genes and splice variants.

17

What are the key proinflammatory cytokines controlled by TCR?

-TNF-alpha
-IL2-5

18

How does the activated T cell make a cytokine?

The expression of cytokine genes is regulated by combinations of different transcription factors.

Non activated T cells: NFAT transcription factor is sitting in cytosol phosphorylated. No expression of genes

TCR activated, TF gets dephosphorylated and translocates to nucleus.

It forms partnerships with other TF (AP-1)in nucleus. The complex binds to promoters of cytokine genes and causes IL2 production.

19

Other responses to TCR activation

TCR activated: There is a cordinated signal.

Cell increases intracellular calcium levels. This activates a phosphatase called calcineurin which dephosphorylates NFAT. NFAT goes to nucleus

It activates nucleotide binding RasGPases protein which then activates MAP kinases and the nuclear component AP1 family Member

20

What is calcineurin?

a phosphatase that in the presence of increases intracellular calcium will dephosphorylate NAFT.

21

What does drug Cyclosporin A and its partner drug FK506 do?

These prevent organ rejection by blocking the T CYTOKINE production of cytokines; the target is the serine phosphatase stopping NFAT going into nucleus.

The major drug used after surgery.

However, cyclosporin A has side effects like damaging kidney, increasing hair, powerful suppressant may increase susceptibility to viral infection.

22

What determines the differentiation of T cells

Signalling pathways induced by cytokines from activated T cells/other innate cells

The cytokine is determined by the pathogens

23

What determines the differentiation/the type of effector of T cells

2 stages: Differentiation itself is initated by detecting antigen (step1) but the type of cell differentiated into is controlled by signalling pathways (step2) induced by cytokines from activated T cells/other innate cells

The cytokine is determined by the pathogen detected

24

What cytokines are needed to differentiate T cells into a Th1 T cell that produces IFN-gamma

IL2, AND IL12

25

What cytokines are needed to differentiate cell into regulatory T cell

IL2

26

What cytokines are needed to differentiate T cells into a Th17 T cell that produces IL-17?

IL6, IL21, IL23

27

What cytokines are needed to differentiate T cells into a Th2 T cell that produces IL-4?

IL4

28

What cytokines are needed to differentiate T cells into a memory T cell of either cytotoxic or helper ?

IL7, IL15

29

What cytokines are needed to differentiate T cells into a cytotoxic cell?

IL2, IL12

30

What are some effects of cytokines?

T cell must have an appropriate cytokine receptor for these cytokines to have their effect.

IL-2: regulates proliferation/differentiation of CD8+/CD4+

IL-4, IL21: needed for Th2 cells and B cells

IL-7: needed for survival of T/B cell progenitors in bone/thymus

IL9: needed for mast cell growth

IL15: needed for NK differentiation and memory T cells.

31

What cytokines are needed to differentiate T cells into a Th2 T cell that produces IL-4?

IL4 made from innate immune cells.

IL4

32

What are the common gamma chain cytokine family?

IL-2
IL4/IL21
IL-7
IL9
IL-15

33

What are the common gamma chain cytokine family?

IL-2
IL4/IL21
IL-7
IL9
IL-15

These cytokines all work by binding to a receptor that contains the common gamma chain.

These receptors only on cell surface if the T cell has seen the original activated T cell and then become activated itself.

34

What is X linked SCID?

Severe Combined Immunodeficiency where there is a mutation of the common gamma chain gene on the X chromosome in Males.

Mother may carry normal wildtype gamma chain, and mutant gamma chain with father with a normal gamma chain. Male offspring with mutant gamma chain will die.

Treatment: bone marrow transplant.

35

Why is the gamma chain of cytokine receptor so important?

gamma chain bind and recruits tyrosine kinase JAK3 which is important for all these cytokines.

(JAK1 binds to beta chain)

36

Which cytokine is important in Thymus T cell development?

IL7: The first T cells acquire IL7 in order to survive in the DP (Double negative stage)

Without IL7, Thymus will not function.

37

Which cytokine controls the growth cycle/proliferation?

IL2: inactivated T cell in blood (G0)

When G0 responds to T cell receptor, it induces expression of IL-2 receptor and makes IL2 cytokine (G1).

IL2 feeds back onto its receptor to make more IL2 (G1-S) and activate other T cells.

Once cells stop making IL2, it still expresses receptor but cell will die via apoptosis.

38

Which cytokine is important in differentiation of all T cells and the size of the T cell?

IL2: it is important in protein synthesis.

39

What is lost in the absence of common gamma chain gene?

-No T cells, No Th2 cells, CD8+
-Incorrect NK, mast cells
-No B cell development
It is needed for human survival.

40

What is TCR (summary)?

It is a multi subunit complex that specific antigen binding subunits (alpha/beta) that are very variable due to gene recombination and can recognise peptide-MHC.

These subunits are linked to signalling chains in CD3 which activate tyrosine kinases in cytosol which set off signalling pathways that change transcription of genes.