Friday, February 12, 2010

JOURNAL CLUB: DNA Methylation controls Foxp3 gene expression

A basic science article was discussed at immunology journal club. It discusses the role of T regs and its how they come from naive T cells and what other factors triggers them.
The vast experiments done elegantly in the study concluded the following:
1. TGF-B induces FoxP3 expression in T regs but its unstable in vitro
2. Azacytidine derivatives( demethylation agent) stabalizes foxp3 expression in induced Tregs.
3. The T reg specific demthylated region (TSDR) determines transcriptional activity
4. Azacytidine promotes stable Foxp3 expression in vitro
5. In vivo induced Tregs exhibit stable Foxp3 expression and complete TSDR demethylation
6. Foxp3 Treg generated invivo by targeting of agonist ligands to dendritic cells showed long term survival in the absence of the inducing antigen and exhibited efficient TSDR demythylation.

Besides the specifics of epigenomic imprinting in the mehylation region of the T cell region which might be critical for T cell lineage, this paper I thought highlighted something very alarming. One is that TGF-B is an important promoter of T reg cells. There are drugs out there currently under development that are inhibitory to TGF-B for anti fibrotic effects. Again, we have to think  of these molecules as possible bimodal and perhaps they have different functions in different disease entities.
Second is that the dendritic cells might be important players in the long term survival of Tregs. Since there are studies that show that the patients that has increase Foxp3+ Tregs, those patients post transplant do better.
Perhaps, sustaining that positive effect should be the goal in transplantation. We can perhaps then achieve tolerance. Perhaps!!
This is interesting to me as a clinician as there might be promise ahead for tolerance.
The article source is here.
A review of the Foxp3 T regs is nicely shown in recent Nature Immunology as well
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