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Gd T-cells regulate transcriptional response to diet in the intestinal epithelium

ABSTRACT: As a site of direct encounter with the external environment, the intestine must balance nutrient uptake with barrier defense. This requires coordination between numerous cell types that engage whole tissue responses to changes in environmental variables. To investigate how nutrient uptake is regulated in the small intestine, we tested the effects of diets with different macronutrient composition on epithelial cell gene expression. We found that expression of enzymes and transporters required for digestion and absorption of carbohydrates, but not protein, was dependent on substrate availability. Surprisingly, the ‘on-demand’ induction of this machinery required gd Tcells, which regulated this program via suppression of IL-22 expression by ILC3s. We found that nutrient availability alters the tissue localization and transcriptome of gd T-cells and that transcriptional responses to diet involved cellular remodeling of the epithelial compartment. This work thus identified a novel role of intestinal gd T-cells in nutrient sensing.

ORGANISM(S): Mus musculus

PROVIDER: GSE145857 | GEO | 2021/03/01

REPOSITORIES: GEO

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Project description:Background: Tissue-resident gd intraepithelial lymphocytes (IELs) orchestrate innate and adaptive immune responses to maintain intestinal epithelial barrier integrity. Epithelia-specific butyrophilin-like (Btnl) molecules induce perinatal development of distinct Vg TCR+ IELs, however, the mechanisms that control gd IEL maintenance within discrete intestinal segments are unclear. Btnl2, a member of Btnl family, has been shown to induce Treg differentiation and suppress T cell activation and proliferation in vitro. Btnl2 is highly enriched in villous IECs across different intestinal compartments and its expression is reported to be altered by inflammatory cues such as epithelial injury and tumor burden. We sought to understand the role of Btnl2 in regulating intestinal immune responses during homeostasis and inflammation and, particularly, in the induction and maintenance of intestinal gd IELs. Methods: We surveyed the gut immune system of in-house generated Btnl2-KO and WT mice within discrete intestinal segments (duodenum, jejunum, ileum, colon) during homeostasis and DSS-induced epithelial injury using flow cytometry, primary cell assays, immunoassays, and gene expression profiling. In addition, we performed high throughput transcriptomic (bulk RNAseq and scRNAseq) and TCR repertoire (scTCRseq) characterization of segment-specific Btnl2-KO and WT gd IELs at steady-state. Results: We characterized newly generated Btnl2 knockout mice and identify a role for Btnl2 in regulating the frequencies and phenotype of gd IELs preferentially in the ileum at steady state. We found that gd IELs derived from the ileum, but not duodenum, of Btnl2-KO mice possess a dysregulated antibacterial response module. By integrating RNA and single-cell TCR expression data we identified distinct transcriptional signatures and greater TCR repertoire diversity in ileal Btnl2-KO gd IELs. Upon DSS challenge, Btnl2-KO mice displayed enhanced colonic, but not ileal, intestinal inflammation and delayed mucosal repair. Conclusions: Collectively, our findings suggest that context-dependent Btnl2 expression fine-tunes intestinal immune responses to protect against epithelial injury. Overall, Btnl-mediated targeting of γδ IEL development and maintenance may help dissect their immunological functions in intestinal diseases with segment-specific manifestations.

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Gd T-cells regulate transcriptional response to diet in the intestinal epithelium

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