Breakout #3 Flashcards
Upon binding cytokine, how do cytokine receptors induce their signals?
JAK/STAT Pathway
What is the function of JAK?
Bind to cytokine receptor and initiate cytokine receptor signaling pathway; also to phosphorylate STAT
How are JAK proteins activated?
Tyrosine phosphorylation
What is the function of STAT proteins?
After homo/heterodimerize with other STAT proteins, STAT will enter into the nucleus and act as a transaction factor
In the Th1 Cell Differentiation pathway, what two cytokines work together to promote CD4+ T cells becoming Th1 cells?
IL-12 and IFN-gamma
What happens after a naive T cell is activated through the TCR and CD28?
NFAT is activation and IFN-gamma binds to the IFN-gamma receptor
Why is IFN-gamma binding to its receptor (IFN-gamma receptor) critical for initiation promotion of Th1 differentiation?
When IFN-gamma binds to its receptor, STAT1 is activated and increases T-bet
What molecule does T-bet drive the production of?
T-bet drives IFN-gamma production
How is the feedback loop of IFN-gamma binding to the IFN-gamma receptor augmented?
The feedback loop of IFN-gamma binding to IFN-gamma receptor is augmented by IL-12 binding to the IL-12 receptor to activate STAT4
What molecules work together as transcription factors to augment T-bet to sufficient levels to permanently establish Th1 differentiation?
STAT4 and STAT1
What is the master-regulator of Th1 cell differentiation?
T-bet
What activates NFAT in Th1 cell differentiation?
Antigen (e.g pathogen) binding to TCR
What two cells secrete IFN-gamma, which stimulates IFN-gamma receptor (thereby: inducing STAT1)?
APC and NK cells
Although low levels of T-bet significantly increases levels of IFN-gamma transcription, what is required for commitment to Th1 phenotype?
High levels of T-bet are required for commitment to Th1 phenotype because it allows for:
a) shutting down IL-4 gene expression
b) alterations to the IFN-gamma promoter
What is the master regulator of Th2 cell differentiation?
GATA-3
How is NFAT activated in Th2 cell differentiation?
Naive T cells are activated via TCR and CD28
If activated CD4+ T cell is activated in the presence of IL-4, binding of IL-4 to its receptor will induce what?
Phosphorylation of STAT6
What induces the expression of GATA-3 (Th2 master regulator)?
STAT6 translocating into the nucleus
How does GATA-3 function?
Binds to promoters of cytokines (IL-4, 5, and 6) and directly shuts down IFN-gamma gene expression
What is ultimately responsible for permanently determine cytokine phenotype of Th cells?
Epigenetic modification of the chromosome
What molecules associate with proteins that modify chromatin structure?
T-bet (Th1) and GATA-3
True or False: The cytokine genes in a CD4+ T cell can be altered in a permanently open or closed state
True
How does removing methylation from DNA affect accessibility of DNA to TF’s
Removing CH3 groups allows DNA to repel each other, increased accessibility to transcription factors
How does acetylation of histones affect accessibility of transcription factors to DNA?
Acetylation increase accessibility of transcription factors to DNA
What two molecules direct the localization of histone acetylases and demethylating enzymes to the Th1 and Th2 promoters?
T-bet and GATA-3
In Th1 cells
- IFN-gamma promoter:
- IL-4 promoter:
In Th2 cells
- IL-4 promoter:
- IFN-gamma promoter:
In Th1 cells
- IFN-gamma promoter: demethylated + acetylated = open
- IL-4 promoter: methylated + deacetylated = closed
In Th2 cells
- IL-4 promoter: demethylated + acetylated = open
- IFN-gamma promoter: methylated + deacetylated = closed
