Lecture 21 - Tregs (pt. 2) Flashcards
what is the Treg proteome?
mRNA that actually gets transcribed
what 2 general signals influence the Treg proteome?
- Foxp3 signaling
- Non-transcriptional signals
how does Foxp3 signaling affect the Treg proteome?
induce suppressive function and block inflammatory genes as part of the Treg transcriptional program
3 examples of non-transcriptional signals that affect Treg proteome
- extracellular signals
- miRNA
- Protein modification
why is it important to look at Treg proteome?
anything can be transcribed, but whether or not it is translated will actually affect the function
why are extracellular signals important for Tregs?
lets them adapt and evolve their function based on level of in situ inflammation
describe what was found in general with polyribosomal profiling
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
3 pathways of genes expressed more in Teff than Treg
- ubiquitination
- chromatin modifications
- cell cycle pathways
describe the importance of different translation activity in diff cells
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
describe the consequence of having specific clusters of mRNA with more ribosomes
the cell type is in a state of readiness and can respond quickly without taking the time to go thru transcription
describe importance of readiness for a Treg
Treg in inflamed site should be able to work quickly
what is an mRNA that is more translationally active in Teff?
eIF-4E
what is eIF-4E used for?
major translation initiation factor –> directs ribosomes to 5’ end of mRNAs and allows for translation of growth and proliferation genes
what is eIF-4E induced by?
growth factors, like IL2
how does IL2 stimulate eIF-4E and the result?
IL2 acts thru PI3K pathway, allowing for production of eIF-4E and which allows for translation of genes involved in growth and metabolism
what does mean that Tregs have plasticity?
they can divert their differentiation / function based on diff cues
what causes Tregs in periphery to become exTregs?
pro-inflammatory cytokines (IL6) due to inflammation or infection can induce Tregs to become ex-tregs
what are exTregs?
T cells that were once regulatory, now have inflammatory cytokines
4 differences in exTreg vs Treg?
- Treg is less stable
- Foxp3 downregulated so supression mechanisms lost
- Tregs can proliferate
- inflammatory phenotype
1 benefit and 1 downside of Tregs becoming exTregs
BENEFIT: in infection will help with response
DOWNSIDE: exTregs are self-responsive and inflammatory so it leads to autoimmunity
2 factors that make exTregs have an inflammatory phenotype
- Th1 and Th17-like
- epigenetic and transcriptional changes
a main difference btwn exTregs and Teff
exTregs are SELF-REACTIVE, Teff are reactive against antigen
in addition to becoming exTregs, what is another piece of evidence that Tregs have plasticity?
Tregs can adapt to the immune response they are regulating by expressing TFs required for a specific T cell response
what happens to Tregs if they are responding to Th1 response?
Tregs will acquire phenotype that mimics Th1 cells and acquire Tbet expression
what happens to Tregs if they are responding to Th2 response?
Tregs will acquire phenotype that mimics Th2 cells and acquire GATA3 expression
what happens to Tregs if they are responding to Th3 response?
Tregs will acquire phenotype that mimics Th17 cells and acquire RORyT expression
3 advantages of T cells mimicking Teff
- Migration
- Survival
- Expansion
describe the enhanced migration in Tregs regulating Th1 responses
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
what educates Tregs whether to engage or not?
tissue damage causes release of alarmins that induces an immune response to educate Tregs
2 examples of alarmins
- IL33
- IL1
describe activity of IL33 on Tregs
IL33 binds Foxp3 Treg at ST2 receptor to POTENTIATE regulation –> Tregs expand and are more fit
describe activity of IL1 on Tregs
IL1 forces Tregs to induce Th17 response and express RORyT –> now become POOR SUPPRESSORS and contribute to fighting immune response
3 types of environmental cues that promote Treg adaptation
- alarmins
- environmental stressors like Na+
- metabolism: glucose/FA
which environmental cues occur and what determines the ultimate Treg response?
all cues happen but context determines quantity of the cues to determine ultimate response
