Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
J Exp Med. 2013 Jun 3;210(6):1069-77. doi: 10.1084/jem.20122695. Epub 2013 May 27.
Membrane-associated RING-CH1 (MARCH1) is an E3 ubiquitin ligase that mediates ubiquitination of MHCII in dendritic cells (DCs). MARCH1-mediated MHCII ubiquitination in DCs is known to regulate MHCII surface expression, thereby controlling DC-mediated T cell activation in vitro. However, its role at steady state or in vivo is not clearly understood. Here, we show that MARCH1 deficiency resulted in a substantial reduction in the number of thymus-derived regulatory T cells (T reg cells) in mice. A specific ablation of MHCII ubiquitination also significantly reduced the number of thymic T reg cells. Indeed, DCs deficient in MARCH1 or MHCII ubiquitination both failed to generate antigen-specific T reg cells in vivo and in vitro, although both exhibited an increased capacity for antigen presentation in parallel with the increased surface MHCII. Thus, MARCH1-mediated MHCII ubiquitination in DCs is required for proper production of naturally occurring T reg cells, suggesting a role in balancing immunogenic and regulatory T cell development.
膜相关环指蛋白 1（MARCH1）是一种 E3 泛素连接酶，可介导树突状细胞（DC）中 MHCII 的泛素化。已知 MARCH1 介导的 DC 中 MHCII 的泛素化可调节 MHCII 表面表达，从而控制体外 DC 介导的 T 细胞激活。然而，其在稳定状态或体内的作用尚不清楚。在这里，我们发现 MARCH1 缺陷导致小鼠胸腺来源的调节性 T 细胞（Treg 细胞）数量显著减少。MHCII 泛素化的特异性缺失也显著减少了胸腺 Treg 细胞的数量。实际上，缺乏 MARCH1 或 MHCII 泛素化的 DC 均未能在体内和体外产生抗原特异性 Treg 细胞，尽管它们均表现出与增加的表面 MHCII 平行的增强的抗原呈递能力。因此，DC 中 MARCH1 介导的 MHCII 泛素化对于天然存在的 Treg 细胞的正常产生是必需的，这表明其在平衡免疫原性和调节性 T 细胞发育方面发挥作用。
