Contribution of Foxp3 to the Treg signature

The transcription factor Foxp3 is usually considered the master regulator for the CD4+CD25+ "Treg" lineage, which plays a key role in controlling immune and autoimmune responses, and is characterized by a unique transcriptional signature. We have performed a meta-analysis of this signature in Treg cells in several conditions to delineate the elements that can be ascribed to T cell activation, TGFbeta signaling, or Foxp3 itself. We find that these influences synergize to activate many of the signatures components. Foxp3 and TGFbeta signaling have interconnected relationships, as Foxp3 is induced by TGFbeta while enhancing TGFbetas positive feedback loop. Much of the Treg signature cannot be ascribed to Foxp3, as it contains gene clusters that are co-regulated, but cannot be transactivated, by Foxp3. This suggests that the Treg lineage is specified at a higher level of regulation, upstream of Foxp3, which does control some of the lineages essential immunoregulatory attributes.

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Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C