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Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewing intestinal inflammation

ABSTRACT: Dysregulation of DNA double-strand break (DSB) repair leads to adaptive immunodeficiency, while the remaining lymphocytes are aberrantly activated and provoke inflammation. To clarify the biological impact of the LIG4 W447C variant identified in our patient, we generated the mutant mice of DNA ligase IV (LIG4), which is critical for DSB repair. Lig4_W447C/W447C mice showed severe intestinal inflammation under adaptive immunodeficiency. The inflammation was featured by a marked infiltration of T helper type 1 (Th1) cells and macrophages. We used scRNA-seq to analyse the detailed splenocyte population and T cell receptor repertoire in Lig4_W447C/W447C mice. Evaluation of the T cell receptor repertoire in Lig4_W447C/W447C mice revealed activated oligoclonal Th1 cells with restricted Vα diversity. Thus, our present results with our novel hypomorphic Lig4 mutant mice show that defective DSB repair leads to Th1-dependent intestinal inflammation under severe adaptive immunodeficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE294169 | GEO | 2026/08/18

REPOSITORIES: GEO

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