Abstract Details

Title Aiolos Silences Il2 Expression and Promotes Th17 Cell Differentiation

Topic MS and Related Diseases

Presentation(s) S50 - (-)

Poster/Presentation
Number 002

Objective

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 TH17 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.

Design/Methods We used Aiolos-deficient mice in in vitro and in vivo experimental 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 identified a module in the transcriptional program of TH17 cells that actively limits IL-2 production and promotes their differentiation.

Authors/Disclosures
Francisco J. Quintana, PhD (Brigham and Women's Hospital/Harvard Medical) PRESENTER	Dr. Quintana has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Ada Yeste	No disclosure on file
	No disclosure on file
	No disclosure on file
Manu Rangachari, PhD	No disclosure on file
	No disclosure on file
	No disclosure on file
Vijay K. Kuchroo, PhD, DVM	Vijay Kuchroo has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tizona. Vijay Kuchroo has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Equillium. Vijay Kuchroo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Vijay Kuchroo has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Vijay Kuchroo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viela Bio. Vijay Kuchroo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kintai. Vijay Kuchroo has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Astellas. Vijay Kuchroo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Equillium. Vijay Kuchroo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Repertoir. Vijay Kuchroo has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cellsius. Vijay Kuchroo has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Genentech. Vijay Kuchroo has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Bicara. Vijay Kuchroo has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Biocon Biologic. Vijay Kuchroo has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Syngene. Vijay Kuchroo has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for McNeill Baur. Vijay Kuchroo has received stock or an ownership interest from Bicara. Vijay Kuchroo has received stock or an ownership interest from Biocon Biologic. Vijay Kuchroo has received stock or an ownership interest from Biolegend. Vijay Kuchroo has received stock or an ownership interest from Celsius. Vijay Kuchroo has received stock or an ownership interest from Equillium. Vijay Kuchroo has received stock or an ownership interest from Syngene. Vijay Kuchroo has received stock or an ownership interest from Tizona. Vijay Kuchroo has received stock or an ownership interest from Alpine Immune Sciences. The institution of Vijay Kuchroo has received research support from Lupus Research Alliance . The institution of Vijay Kuchroo has received research support from F. Hoffmann-LaRoche Ltd.. The institution of Vijay Kuchroo has received research support from Sanofi/Genzyme . The institution of Vijay Kuchroo has received research support from Nancy Davis Innovation Award . The institution of Vijay Kuchroo has received research support from NIH. Vijay Kuchroo has received intellectual property interests from a discovery or technology relating to health care.

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