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The DNA endonuclease Apex1 ensures a cytopathic T cell fate in autoimmunity by mediating DNA base excision and repair 2638

Year: 2025
Type: article
Abstract: Description T cells experience significant DNA damage during clonal expansion, particularly due to reactive oxygen species, which create baseless DNA sites that threaten genomic stability. In this study, we identify the apurinic/apyrimidinic endonuclease-1 (Apex1) as an essential base repair enzyme that preserves DNA integrity, thereby enabling T cells to attain cytopathic functions critical for autoimmune and inflammatory responses. By conditionally deleting Apex1 in T cells, we demonstrate that Apex1-deficient T cells accumulate baseless DNA sites, leading to genomic instability and apoptotic cell death. As a result, Apex1-deficient mice are protected from experimental autoimmune encephalomyelitis (EAE) and allergic lung inflammation, with T cells unable to develop effector phenotypes or produce pro-inflammatory cytokines. Mutational analysis reveals that the DNA endonuclease activity of Apex1 is essential for T cell proliferation, while its redox function is dispensable. Notably, pharmacologic inhibition of Apex1’s DNA repair activity, but not its redox function, effectively mitigates autoimmune disease progression. This study establishes Apex1 as a vital regulator of effector T cell fate, emphasizing the importance of DNA repair in supporting T cell responses under metabolic and oxidative stress. Our findings suggest that targeting Apex1’s DNA repair function presents a novel strategy for treating autoimmune and inflammatory diseases where pathogenic T cells are critically involved. Funding Sources R01AI129906 to XCL, R01AI132492 to WC, and R01AI155488 to ZZ Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
DOI: 10.1093/jimmun/vkaf283.536
Institution: Houston Methodist
Language: English
Open Access status: bronze
OpenAlex ID: W4416449790
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