
Ctla-4 결핍은 제브라피시에서 염증성 장 질환과 유사한 표현형을 유발하며, 이는 Ctla-4가 장내 면역 항상성 유지에 필수적인 역할을 한다는 것을 보여줌.


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Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient ( ctla-4-/- ) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.

### Competing Interest Statement

The authors have declared no competing interest.

All data generated or analyzed during this study are included in this article and its supplementary information files. The RNA-seq and scRNA-seq data for this study have been deposited in NCBI Gene Expression Omnibus (GEO) (<https://www.ncbi.nlm.nih.gov/geo/>) under accession numbers GSE255304 and GSE255303, respectively. The 16S rRNA sequencing data in this study have been deposited in the NCBI Sequence Read Archive (SRA) (<https://www.ncbi.nlm.nih.gov/sra/>) with an accession number of BioProject PRJNA1073727.

Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease

장내-면역-항상성-유지에서-ctla-4의-역할-규명-염증성-장-질환-제브라피시-모델로부터의-통찰


장내 면역 항상성 유지에서 Ctla-4의 역할 규명: 염증성 장 질환 제브라피시 모델로부터의 통찰
