Aiolos Silences Il2 Expression and Promotes Th17 Cell Differentiation

Background: Th17 cells are instrumental in the immune response to pathogens, but can also drive tissue inflammation and autoimmunity. Therefore it is important to identify the molecular mechanisms that control the development of T_H17 cells.  Our transcriptional studies found that the transcription factor Aiolos is upregulated during Th17-cell differentiation.  Thus, we investigated the role of Aiolos in Th17 cells.

Objectives: The aim of this study was to study the molecular pathways controlling the differentiation of encephalitogenic IL-17 producing CD4⁺T (Th17) cells.

Methods: We used Aiolos-deficient mice in in vitro and in vivoexperimental systems to investigate the role of Aiolos in Th17 cells.  We also used time-course analyses of gene expression, reporter assays and chromatin immunoprecipitation assays to characterize the transcriptional network regulating Aiolos expression, and its role in controlling the epigenetic status of Th17 cells.

Results: We found that under Th17-polarizing conditions the transcription factors STAT3 and AhR upregulate the expression of Aiolos. Aiolos deficiency ted to a decrease in epigenetic marks linked to the silencing of the il2 locus, an increased production of IL-2 and an impaired differentiation of Th17 cells in vitro and in vivo.  Moreover, this reduced polarization into Th17 cells could be reversed with IL-2 specific blocking antibodies.   Conversely, Aiolos-deficient T cells showed an increased polarization into Th1 cells, which was also dependent of IL-2.  In vivo, Aiolos-deficient Th17 cells showed a decreased ability to transfer EAE, but showed and increased ability to transfer EAE when polarized under Th1 conditions. Taken together, these data suggest that Aiolos controls the epigenetic status of the Il2 locus, actively inhibiting IL-2 production and promoting the differentiation of Th17 cells in vitro and in vivo.

Conclusions: We have identified a module in the transcriptional program of T_H17 cells that actively limits IL-2 production and promotes their differentiation.