Division of Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010.
Department of Pediatrics-Neonatology, University of California, Los Angeles, CA 90095.
J Immunol. 2018 Jul 15;201(2):440-450. doi: 10.4049/jimmunol.1701654. Epub 2018 May 23.
Th17 cells are a class of Th cells that secrete IL-17 and mediate pathogenic immunity responsible for autoimmunity including experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Retinoic acid-related orphan receptor γ t (RORγt) is the critical transcription factor that controls the differentiation of Th17 cells. However, little is known about the transcriptional cofactors for RORγt in the regulation of Th17 differentiation. In this study, we demonstrate that protein arginine -methyltransferase 1 (PRMT1) associates with RORγt and regulates mouse Th17 differentiation. Overexpression of PRMT1 promoted Th17 differentiation, whereas inactivation or knockdown of PRMT1 decreased Th17 differentiation while expanding Foxp3 regulatory T cells. Consistently, pharmacological inhibition of PRMT1 impaired the generation of Th17 cells and prevented induction of experimental autoimmune encephalomyelitis in mice. Mechanistically, PRMT1-dependent modification of asymmetric histone 4 arginine 3 dimethylation is required to stabilize the stimulatory STAT3 to displace the inhibitory STAT5 at IL-17 locus, resulting in the activation of IL-17 gene. Furthermore, PRMT1-facilitated recruitment of STAT3 overcame the inhibition of Th17 differentiation exerted by IL-2-induced STAT5 activation. PRMT1 thus regulates Th17 differentiation by controlling the reciprocal recruitment of STAT3 and STAT5. Our study thus reveals PRMT1 as a novel target for alleviating Th17-mediated autoimmunity by decreasing RORγ-dependent generation of pathogenic Th17 cells.
Th17 细胞是一类分泌白细胞介素-17（IL-17）并介导致病性免疫的 Th 细胞，负责自身免疫，包括实验性自身免疫性脑脊髓炎，多发性硬化症的一种啮齿动物模型。维甲酸相关孤儿受体γ t（RORγt）是控制 Th17 细胞分化的关键转录因子。然而，关于 RORγt 在 Th17 分化调节中的转录共因子知之甚少。在这项研究中，我们证明了蛋白精氨酸 N-甲基转移酶 1（PRMT1）与 RORγt 相关，并调节小鼠 Th17 分化。PRMT1 的过表达促进 Th17 分化，而 PRMT1 的失活或敲低减少 Th17 分化，同时扩大 Foxp3 调节性 T 细胞。一致地，PRMT1 的药理学抑制破坏了 Th17 细胞的产生，并防止了实验性自身免疫性脑脊髓炎在小鼠中的诱导。在机制上，PRMT1 依赖性修饰不对称组蛋白 4 精氨酸 3 二甲基化是稳定刺激 STAT3 的必需的，以取代 IL-17 基因座处的抑制性 STAT5，从而激活 IL-17 基因。此外，PRMT1 促进的 STAT3 募集克服了由 IL-2 诱导的 STAT5 激活引起的 Th17 分化抑制。PRMT1 因此通过控制 STAT3 和 STAT5 的相互募集来调节 Th17 分化。因此，我们的研究揭示了 PRMT1 作为通过减少 RORγ 依赖性致病性 Th17 细胞产生来减轻 Th17 介导的自身免疫的新靶标。
