Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [ATAC-seq]

Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions. Global chromatin accessibility profiling of Aiolos-deficient IEL and control cells