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Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial ?? T cell compartments.

ABSTRACT: Butyrophilin-like (Btnl) genes are emerging as major epithelial determinants of tissue-associated ?? T cell compartments. Thus, the development of signature, murine TCR??+ intraepithelial lymphocytes (IEL) in gut and skin depends on Btnl family members, Btnl1 and Skint1, respectively. In seeking mechanisms underlying these profound effects, we now show that normal gut and skin ?? IEL development additionally requires Btnl6 and Skint2, respectively, and furthermore that different Btnl heteromers can seemingly shape different intestinal ??+ IEL repertoires. This formal genetic evidence for the importance of Btnl heteromers also applied to the steady-state, since sustained Btnl expression is required to maintain the signature TCR.V?7+ IEL phenotype, including specific responsiveness to Btnl proteins. In sum, Btnl proteins are required to select and to maintain the phenotypes of tissue-protective ?? IEL compartments, with combinatorially diverse heteromers having differential impacts on different IEL subsets.

SUBMITTER: Jandke A

PROVIDER: S-EPMC7387338 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments.

Jandke Anett A Melandri Daisy D Monin Leticia L Ushakov Dmitry S DS Laing Adam G AG Vantourout Pierre P East Philip P Nitta Takeshi T Narita Tomoya T Takayanagi Hiroshi H Feederle Regina R Hayday Adrian A

Nature communications 20200728 1

Butyrophilin-like (Btnl) genes are emerging as major epithelial determinants of tissue-associated γδ T cell compartments. Thus, the development of signature, murine TCRγδ<sup>+</sup> intraepithelial lymphocytes (IEL) in gut and skin depends on Btnl family members, Btnl1 and Skint1, respectively. In seeking mechanisms underlying these profound effects, we now show that normal gut and skin γδ IEL development additionally requires Btnl6 and Skint2, respectively, and furthermore that different Btnl ...[more]

PMID: 32724083

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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.

Dataset Information

Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial ?? T cell compartments.

Publications

Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments.

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