Division of Gastroenterology and Hepatology, the Third Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan ; Department of Molecular Genetics, Institute of Biomedical Science, and Core Research for Engineering, Science and Technology, Japan Science and Technology Agency, Kansai Medical University, Hirakata, Osaka, Japan.
PLoS One. 2013 Sep 9;8(9):e73874. doi: 10.1371/journal.pone.0073874. eCollection 2013.
Although the cell-to-cell contact between CD4(+)Foxp3(+) regulatory T (Treg) and their target cells is important for the suppressor function of Treg cells, the regulation of this process is not well understood. Here we show that the Mst1 kinase plays a critical role in the suppressor function of Treg cells through regulation of cell contact dependent processes. Mst1 (-/-) Treg cells failed to prevent the development of experimental colitis and antigen-specific suppression of naïve T cells proliferation in vitro. Mst1 (-/-) Treg cells exhibited defective interactions with antigen-presenting dendritic cells (DCs), resulting in reduced down-regulation of costimulatory molecules. While wild-type CD4(+) Foxp3(+) Treg cells formed mobile immunological synapses on supported planar membrane, Mst1 (-/-) Treg cells did not exhibit ICAM-1 ring or central peptide-MHC clustering. Using two-photon imaging we showed that antigen-specific wild-type Treg cells exhibited dynamic mobile contacts with antigen-pulsed DCs bearing stably associated naïve T cells. In contrast, Mst1 (-/-) Treg had impairments in their interactions with DCs. Thus, Mst1 is required for Treg cells to mediate contact-dependent suppressor functions.
尽管 CD4(+)Foxp3(+)调节性 T（Treg）细胞与其靶细胞之间的细胞间接触对于 Treg 细胞的抑制功能很重要，但该过程的调控机制尚不清楚。在这里，我们表明，Mst1 激酶通过调节细胞接触依赖性过程，在 Treg 细胞的抑制功能中发挥关键作用。Mst1（-/-）Treg 细胞未能预防实验性结肠炎的发展，也未能在体外抑制幼稚 T 细胞的抗原特异性增殖。Mst1（-/-）Treg 细胞与抗原呈递树突状细胞（DC）的相互作用存在缺陷，导致共刺激分子的下调减少。虽然野生型 CD4(+)Foxp3(+)Treg 细胞在支持的平面膜上形成可移动的免疫突触，但 Mst1（-/-）Treg 细胞没有表现出 ICAM-1 环或中央肽 MHC 聚类。通过双光子成像，我们发现抗原特异性野生型 Treg 细胞与携带稳定结合的幼稚 T 细胞的抗原脉冲 DC 之间表现出动态的可移动接触。相比之下，Mst1（-/-）Treg 细胞在与 DC 的相互作用中存在缺陷。因此，Mst1 是 Treg 细胞介导依赖接触的抑制功能所必需的。
