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Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE220030 | GEO | 2023/10/20

REPOSITORIES: GEO

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Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [CUT&RUN]

Project description: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.

2023-10-20 | GSE220022 | GEO

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

2023-10-20 | GSE220021 | GEO

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

2023-10-20 | GSE220020 | GEO

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

2023-10-20 | GSE220028 | GEO

Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes

Project description:Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes

| PRJNA908085 | ENA

Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [CUT&RUN]

Project description:Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [CUT&RUN]

| PRJNA908089 | ENA

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

Project description:Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [scRNA-seq]

| PRJNA908090 | ENA

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

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

| PRJNA908082 | ENA

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

Project description:Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [RNA-seq]

| PRJNA908083 | ENA

The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes.

Project description:Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3-/- CD8αα+ IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3-/- and Ikzf3+/+ IELs showed an amplified effector machinery in Ikzf3-/- CD8αα+ IELs compared to Ikzf3+/+ counterparts. Ikzf3-/- CD8αα+ IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.

| S-EPMC11835375 | biostudies-literature

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