Hashimoto-Tane Akiko, Sakuma Machie, Ike Hiroshi, Yokosuka Tadashi, Kimura Yayoi, Ohara Osamu, Saito Takashi
Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
J Exp Med. 2016 Jul 25;213(8):1609-25. doi: 10.1084/jem.20151088. Epub 2016 Jun 27.
The immunological synapse (IS) formed at the interface between T cells and antigen-presenting cells represents a hallmark of initiation of acquired immunity. T cell activation is initiated at T cell receptor (TCR) microclusters (MCs), in which TCRs and signaling molecules assemble at the interface before IS formation. We found that each TCR-MC was transiently bordered by a ring structure made of integrin and focal adhesion molecules in the early phase of activation, which is similar in structure to the IS in microscale. The micro-adhesion ring is composed of LFA-1, focal adhesion molecules paxillin and Pyk2, and myosin II (MyoII) and is supported by F-actin core and MyoII activity through LFA-1 outside-in signals. The formation of the micro-adhesion ring was transient but especially sustained upon weak TCR stimulation to recruit linker for activation of T cells (LAT) and SLP76. Perturbation of the micro-adhesion ring induced impairment of TCR-MC development and resulted in impaired cellular signaling and cell functions. Thus, the synapse-like structure composed of the core TCR-MC and surrounding micro-adhesion ring is a critical structure for initial T cell activation through integrin outside-in signals.
T细胞与抗原呈递细胞界面处形成的免疫突触(IS)是获得性免疫启动的标志。T细胞活化始于T细胞受体(TCR)微簇(MCs),在IS形成之前,TCR和信号分子在该界面处组装。我们发现,在活化早期,每个TCR-MC都被由整合素和粘着斑分子构成的环形结构短暂包围,该结构在微观尺度上与IS结构相似。微粘附环由淋巴细胞功能相关抗原-1(LFA-1)、粘着斑分子桩蛋白和脯氨酸富集酪氨酸激酶2(Pyk2)以及肌球蛋白II(MyoII)组成,并通过LFA-1的外向内信号由F-肌动蛋白核心和MyoII活性支撑。微粘附环的形成是短暂的,但在弱TCR刺激下尤其持续,以募集T细胞活化连接蛋白(LAT)和SH2结构域含磷蛋白76(SLP76)。微粘附环的扰动导致TCR-MC发育受损,并导致细胞信号传导和细胞功能受损。因此,由核心TCR-MC和周围微粘附环组成的突触样结构是通过整合素外向内信号进行初始T细胞活化的关键结构。