
Ctla-4は腸内免疫恒常性の維持に不可欠な役割を果たす。Ctla-4欠損はゼブラフィッシュにおいて炎症性腸疾患様の表現型を引き起こす。


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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

腸内免疫恒常性におけるctla-4の役割の解明-炎症性腸疾患の新規ゼブラフィッシュモデルからの洞察


腸内免疫恒常性におけるCtla-4の役割の解明：炎症性腸疾患の新規ゼブラフィッシュモデルからの洞察
