Lecture 21 - Tregs (pt. 2)

Question 1

what is the Treg proteome?

Answer 1

mRNA that actually gets transcribed

Question 2

what 2 general signals influence the Treg proteome?

Answer 2

1. Foxp3 signaling
2. Non-transcriptional signals

Question 3

how does Foxp3 signaling affect the Treg proteome?

Answer 3

induce suppressive function and block inflammatory genes as part of the Treg transcriptional program

Question 4

3 examples of non-transcriptional signals that affect Treg proteome

Answer 4

1. extracellular signals
2. miRNA
3. Protein modification

Question 5

why is it important to look at Treg proteome?

Answer 5

anything can be transcribed, but whether or not it is translated will actually affect the function

Question 6

why are extracellular signals important for Tregs?

Answer 6

lets them adapt and evolve their function based on level of in situ inflammation

Question 7

describe what was found in general with polyribosomal profiling

Answer 7

found some mRNAs have more ribosomes associated, other mRNAs have no ribosomes

there are genes for specific functions where mRNAs are translated differently in different cell types

Question 8

3 pathways of genes expressed more in Teff than Treg

Answer 8

1. ubiquitination
2. chromatin modifications
3. cell cycle pathways

Question 9

describe the importance of different translation activity in diff cells

Answer 9

even if genes are transcribed in 2 diff cells at the same time and to the same extent, translation allows 1 cell type to be silenced and the other to be active –> specific proteins can be readily available

Question 10

describe the consequence of having specific clusters of mRNA with more ribosomes

Answer 10

the cell type is in a state of readiness and can respond quickly without taking the time to go thru transcription

Question 11

describe importance of readiness for a Treg

Answer 11

Treg in inflamed site should be able to work quickly

Question 12

what is an mRNA that is more translationally active in Teff?

Answer 12

eIF-4E

Question 13

what is eIF-4E used for?

Answer 13

major translation initiation factor –> directs ribosomes to 5’ end of mRNAs and allows for translation of growth and proliferation genes

Question 14

what is eIF-4E induced by?

Answer 14

growth factors, like IL2

Question 15

how does IL2 stimulate eIF-4E and the result?

Answer 15

IL2 acts thru PI3K pathway, allowing for production of eIF-4E and which allows for translation of genes involved in growth and metabolism

Question 16

what does mean that Tregs have plasticity?

Answer 16

they can divert their differentiation / function based on diff cues

Question 17

what causes Tregs in periphery to become exTregs?

Answer 17

pro-inflammatory cytokines (IL6) due to inflammation or infection can induce Tregs to become ex-tregs

Question 18

what are exTregs?

Answer 18

T cells that were once regulatory, now have inflammatory cytokines

Question 19

4 differences in exTreg vs Treg?

Answer 19

1. Treg is less stable
2. Foxp3 downregulated so supression mechanisms lost
3. Tregs can proliferate
4. inflammatory phenotype

Question 20

1 benefit and 1 downside of Tregs becoming exTregs

Answer 20

BENEFIT: in infection will help with response

DOWNSIDE: exTregs are self-responsive and inflammatory so it leads to autoimmunity

Question 21

2 factors that make exTregs have an inflammatory phenotype

Answer 21

1. Th1 and Th17-like
2. epigenetic and transcriptional changes

Question 22

a main difference btwn exTregs and Teff

Answer 22

exTregs are SELF-REACTIVE, Teff are reactive against antigen

Question 23

in addition to becoming exTregs, what is another piece of evidence that Tregs have plasticity?

Answer 23

Tregs can adapt to the immune response they are regulating by expressing TFs required for a specific T cell response

Question 24

what happens to Tregs if they are responding to Th1 response?

Answer 24

Tregs will acquire phenotype that mimics Th1 cells and acquire Tbet expression

Question 25

what happens to Tregs if they are responding to Th2 response?

Answer 25

Tregs will acquire phenotype that mimics Th2 cells and acquire GATA3 expression

Question 26

what happens to Tregs if they are responding to Th3 response?

Answer 26

Tregs will acquire phenotype that mimics Th17 cells and acquire RORyT expression

Question 27

3 advantages of T cells mimicking Teff

Answer 27

1. Migration
2. Survival
3. Expansion

Question 28

describe the enhanced migration in Tregs regulating Th1 responses

Answer 28

by upregulating Tbet to mimic Th1 cells, there will be more CXCR3 on the cell surface so the cell becomes more efficient at going from LN to tissue to fight Th1 cells

Question 29

what educates Tregs whether to engage or not?

Answer 29

tissue damage causes release of alarmins that induces an immune response to educate Tregs

Question 30

2 examples of alarmins

Answer 30

1. IL33
2. IL1

Question 31

describe activity of IL33 on Tregs

Answer 31

IL33 binds Foxp3 Treg at ST2 receptor to POTENTIATE regulation –> Tregs expand and are more fit

Question 32

describe activity of IL1 on Tregs

Answer 32

IL1 forces Tregs to induce Th17 response and express RORyT –> now become POOR SUPPRESSORS and contribute to fighting immune response

Question 33

3 types of environmental cues that promote Treg adaptation

Answer 33

1. alarmins
2. environmental stressors like Na+
3. metabolism: glucose/FA

Question 34

which environmental cues occur and what determines the ultimate Treg response?

Answer 34

all cues happen but context determines quantity of the cues to determine ultimate response