Wang Liwei, Noyer Lucile, Jishage Miki, Wang Yin-Hu, Tao Anthony Y, McDermott Maxwell, Gando Ivan, Sidhu Ikjot, Hu Ke, Zhong Li, Sun Katherine, Drmic Dominik, Kaufmann Ulrike, Feske Stefan
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Sci Immunol. 2025 Jun 20;10(108):eadq8860. doi: 10.1126/sciimmunol.adq8860.
Pathogenic CD4 T cells drive autoimmunity in diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Through a forward genetic screen, we identified chloride nucleotide-sensitive channel 1A (CLNS1A) as a key regulator of inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS. CLNS1A is expressed in several subsets of CD4 T cells, including pathogenic T helper 17 (pT17) cells. Deletion of in T cells resulted in DNA damage, cell cycle arrest, impaired T cell proliferation, and effector function, thereby protecting mice from both EAE and IBD. We found that CLNS1A interacts with protein arginine methyl transferase 5 (PRMT5). Moreover, CLNS1A regulates symmetric histone dimethylation and the expression of genes involved in DNA repair, replication, and cell cycle progression. Thus, CLNS1A plays an important role in CD4 T cells by promoting genome stability and cell cycle progression.
致病性CD4 T细胞在诸如多发性硬化症（MS）和炎症性肠病（IBD）等疾病中驱动自身免疫。通过正向遗传学筛选，我们确定氯离子核苷酸敏感通道1A（CLNS1A）是MS实验性自身免疫性脑脊髓炎（EAE）模型中炎症的关键调节因子。CLNS1A在包括致病性辅助性T细胞17（pT17）细胞在内的多个CD4 T细胞亚群中表达。T细胞中CLNS1A的缺失导致DNA损伤、细胞周期停滞、T细胞增殖受损和效应功能受损，从而保护小鼠免受EAE和IBD的侵害。我们发现CLNS1A与蛋白质精氨酸甲基转移酶5（PRMT5）相互作用。此外，CLNS1A调节对称组蛋白二甲基化以及参与DNA修复、复制和细胞周期进程的基因的表达。因此，CLNS1A通过促进基因组稳定性和细胞周期进程在CD4 T细胞中发挥重要作用。
