Growing evidence indicates that arsenic can cause long-lasting and irreversible damage to the function of the human immune system. It is known that forkhead box protein 3(Foxp3), which is specifically expressed in regulatory T cells (Tregs), plays a decisive role in immunoregulation and is regulated by DNA methylation. While evidence suggests that epigenetic regulated Foxp3 is involved in the immune disorders caused by arsenic exposure, the specific mechanism remains unclear. In this study, after primary human lymphocytes were treated with different doses of NaAsO₂, our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35), and increasing the ratio of CD4⁺/CD8⁺ T cells in lymphocytes. Treatment with DNA methyltransferase inhibitor 5-Aza-CdR can notably inhibit the expression of DNMT1, effectively restoring the hypermethylation of the Foxp3 promoter region in primary human lymphocytes and upregulating the expression levels of Foxp3, balancing the ratio of CD4⁺/CD8⁺ T cells in lymphocytes. It also activates the secretion of anti-inflammatory cytokines and restores the immune regulatory functions of Tregs. In conclusion, our study provides limited evidence that DNMT1-mediated Foxp3 gene promoter hypermethylation is involved in immune dysfunction caused by arsenic in primary human lymphocytes. The study can provide a scientific basis for further understanding the arsenic-induced immune dysfunction in primary human lymphocytes.

中文翻译：

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DNMT1 介导的 Foxp3 基因启动子高甲基化参与砷引起的人淋巴细胞免疫功能障碍。

越来越多的证据表明，砷会对人体免疫系统的功能造成持久且不可逆转的损害。众所周知，在调节性T细胞（Tregs）中特异性表达的叉头盒蛋白3（Foxp3）在免疫调节中起决定性作用，并受DNA甲基化调控。虽然有证据表明表观遗传调节的 Foxp3 与砷暴露引起的免疫紊乱有关，但具体机制仍不清楚。在本研究中，用不同剂量的 NaAsO ₂处理原代人淋巴细胞后，我们的结果表明，砷诱导DNMT1和Foxp3基因启动子甲基化水平的高表达，从而抑制Foxp3的表达水平，随后降低Tregs并减少相关的抗炎细胞因子，如白细胞介素10（IL-10）和白细胞介素10 (IL-35)，并增加淋巴细胞中 CD4 ⁺ /CD8 ⁺ T 细胞的比例。DNA甲基转移酶抑制剂5-Aza-CdR处理可显着抑制DNMT1的表达，有效恢复原代人淋巴细胞Foxp3启动子区域的高甲基化，上调Foxp3的表达水平，平衡CD4 ⁺ /CD8 ⁺的比例淋巴细胞中的 T 细胞。它还激活抗炎细胞因子的分泌，恢复Tregs的免疫调节功能。总之，我们的研究提供了有限的证据，表明 DNMT1 介导的 Foxp3 基因启动子高甲基化与原代人淋巴细胞中砷引起的免疫功能障碍有关。该研究可为进一步了解砷诱导的人类原代淋巴细胞免疫功能障碍提供科学依据。