Since, I have a long-lasting interest in the Ikaros family members, and a more recent one on IL-17 production, I do not resist making an entry on this article: Aiolos promotes Th17 differentiation by directly silencing Il2 expression.
It is clearly established that IL-2 inhibits Th17 differentiation, by interfering with IL-6-dependent signaling events, such as by downregulating expression of the IL-6R. IL-2 also triggers the replacement of STAT3 with STAT5 on target DNA-binding sites in the Il17a-Il17f locus and in other genes required for Th17 differentiation and thus it interferes with the Th17 transcriptional program.
Thus, Th17 differentiation requires active modulation of IL-2 expression both by cell-extrinsic and cell-intrinsic mechanisms.
The present paper from Kuchroo’s lab shows that, through STAT3 and AhR induction, Aiolos bounds to and silences the Il2 locus, suppressing the production of IL-2 and promoting Th17 differentiation in vitro and in vivo.
The members of the Ikaros family are quite interesting since they directly promote transcription on some loci, but also have a strong impact on chromatin modification and can also actively silence genes by associating them to centromeric heterochromatin regions. And indeed, in Aiolos-deficient Th17 cells, the Il2 promoter was characterized by epigenetic modifications associated with active gene expression.
This is a formal demonstration of a role for an Ikaros family member in T cell differentiation.
Ikaros has been previously involved in Th2 differentiation and IL-10 production, Eos in Treg development and now Aiolos promotes Th17.
Given, that the Ikaros family members are prone to homo- but also hetero-dimerisation it is now important to understand whether they work alone to accomplish these functions or if they act in partnership. For instance, Aiolos and Eos seem to be co-expressed in Treg cells, so it is likely that they participate in the control of endogenous IL-2 production in Treg cells.
It is not because only Aiolos is up-regulated during Th17 differentiation that other Ikaros members could not be already present and their function modified by the induction of expression of Aiolos. Indeed, Aiolos-deficiency does not completely abrogate IL-17 production in T cells and this may leave room for cooperation with other transcription factors yet to identify.