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Dietary antigens drive the generation of functional cytotoxic intraepithelial lymphocytes for early defense against foodborne pathogens

ABSTRACT: Intraepithelial lymphocytes (IELs) constitute the largest lymphocyte population in the body and exhibit direct cytotoxic effector functions. How IELs are generated and maintained as effector T cells, however, is poorly understood. While significant attention has been given to the role of commensal microbiota in the intestine, the predominance of dietary components in the small intestine suggests that dietary antigens may regulate IEL generation and homeostasis. Here, we show that conventional TCRab + CD4 + and CD8 + IEL populations are present in normal numbers in germ-free (GF) mice which lack microbiota.However, these IELs are severely depleted in antigen-free (AF) mice, GF mice fed an amino acid diet devoid of proteins. Moreover, the few remaining IELs in AF mice lack effector function. Notably, while TCRab + CD8ab + IELs in adult GF mice can persist for prolonged periods, they lose their effector function when fed an AF diet. IL-12 presumably produced by intestinal dendritic cells plays a critical role in the maintenance of TCRab + CD8ab + IELs and their effector functions. Importantly, mice lacking functional dietary antigen-induced TCRab + CD8ab + IELs exhibit a defect in early protection against a foodborne pathogen, Listeria monocytogenes. Collectively, these findings support that dietary antigen exposure drives the generation of innate-like cytotoxic IELs thatprovide rapid and local protection against foodborne-pathogens.

ORGANISM(S): Mus musculus

PROVIDER: GSE299783 | GEO | 2026/01/28

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.

			Action	DRS
		Other
	GSE299783_DEG_GFvsAF.csv.gz	Csv
	GSE299783_DEG_SPFvsGF.csv.gz	Csv
	GSE299783_genes.FPKM.DC.csv.gz	Csv

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Dietary antigens drive the generation of functional cytotoxic intraepithelial lymphocytes for early defense against foodborne pathogens

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