Abstracts (complete list) - Wissenschaft Online

Karsten Kretschmer, Alexander Marson, Garrett M. Frampton, Julia Polansky, Richard
A. Young, Harald von Boehmer
Foxp3-dependent gene regulation requires T cell activation
Foxp3-expressing CD4+CD25+ regulatory T cells play an essential role in the regulation
of immune responses under physiological conditions. While the function of Foxp3 in Treg
lineage specification has been firmly established, the molecular pathways involved in
the Foxp3-specified developmental and suppressor program are still poorly understood.
Here we report on new evidence that T cell receptor signaling strength greatly
influences the induction of Foxp3 expression in initially naïve CD4+Foxp3- T cells.
Consistent with in vivo experiments, lack of co-stimulation (e.g. via CD28) or inhibition
of T cell receptor-emanating signals during the conversion process enhances TGF-beta
dependent induction of Foxp3 expression in vitro. In addition, global gene expression
profiling in conjunction with genome-wide DNA based location analysis (ChIP-on-Chip)
using custom-spotted tiling arrays, which interrogated Foxp3 binding to 5’ promoters of
approximately 16000 annotated mouse genes, indicated that Foxp3 had very little effect
on gene expression in un-stimulated T cells. In contrast, stimulated Foxp3- and Foxp3+
T cells exhibited significant differences in expression of almost 1% of mouse genes.
Although we found that Foxp3 could also function to activate gene expression, the
predominant effect of Foxp3 promoter occupancy was to suppress the NFAT-dependent
activation of target genes upon T cell stimulation. Consistently, Foxp3-bound promoters
were enriched for NFAT binding sites.