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Microbiota promote enhanced CD39 expression in gd intraepithelial lymphocytes through the activation of TCR and IL-15 signaling.

ABSTRACT: Intraepithelial lymphocytes expressing the gd T cell receptor (gd IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative gd IEL (gdHYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory gd T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39neg gd IEL to a more mature, tissue-adapted CD39hi IEL population. We find that TCRgd activation drives CD122-mediated CD39 upregulation on gdHYP IELs and increased mucosal IL-15 further amplifies CD39 expression in gdHYP IELs. Notably, CD39 induction requires sustained exposure to the gdHYP-associated microbiota. Increased IL-15 signaling prolongs IEL survival and enhances gdHYP IEL bioenergetic potential. Notably, CD39hi gd IELs produce less pro-inflammatory cytokine, which may explain the lack of histopathology in gdHYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on gdHYP IELs, leading to the expansion of gd IELs with regulatory potential.

ORGANISM(S): Mus musculus

PROVIDER: GSE304526 | GEO | 2025/08/05

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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Microbiota promote enhanced CD39 expression in gd intraepithelial lymphocytes through the activation of TCR and IL-15 signaling.

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