Regulation and function of absent in melanoma 2 in human CD4 T cells (IRM7P.710)

Abstract

Abstract Recognition of dsDNA by absent in melanoma 2 (AIM2) leads to inflammasome formation, activation and secretion of IL-1β and IL-18 in innate cells. While AIM2 inflammasome function has been well characterized in macrophages, it has not been explored in adaptive cells. Recently, we have shown that human CD4 T cells robustly upregulate expression of AIM2 following T cell activation. Interestingly, memory CD4 T cells have a higher resting level of expression of AIM2 and more rapid upregulation of AIM2 mRNA following activation. High-throughput targeted bisulfite sequencing and ChIPseq show that AIM2 expression in CD4 T cells is epigenetically regulated by DNA methylation and histone modifications. The AIM2 promoter exhibits both hypomethylated CpGs and increased H3K4me3 and H3K4me2 in memory CD4 T cells compared to naïve. Such epigenetic marks allow for both a higher basal level of AIM2 expression and stronger induction of AIM2 expression following T cell activation. Robust protein expression of AIM2 is also found following stimulation of these cells. While AIM2 is known to form inflammasomes and drive IL-1β and IL-18 expression in macrophages, CD4 T cells do not express either of these cytokines, suggesting a non-canonical role for AIM2 function in T cells. Our current studies are focused on determining the function of AIM2 in CD4 T cells, and preliminary work suggests that AIM2 plays a role in the regulation of apoptosis following T cell receptor crosslinking