Hara Satoru, Nakaseko Chiaki, Yamasaki Sho, Hattori Masakazu, Bos Johannes L, Saito Yasushi, Minato Nagahiro, Saito Takashi
Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Hematology. 2009 Jun;14(3):150-8. doi: 10.1179/102453309X402241.
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell co-stimulation receptor that delivers inhibitory signals upon activation. This inhibitory effect by CTLA-4 requires activation of small GTPase Rap-1. However, the precise mechanism underlying these negative signals remains unclear. Here, we show that CTLA-4-induced suppression of IL-2 production correlates with rapid destabilization of immunological synapse (IS) formation in murine normal T cell clones. Overexpression of Spa-1, a Rap-1-specific GTPase activating protein (GAP), abolished both Rap-1 activation and IL-2 suppression induced by CTLA-4. Although we failed to find any specific inhibition of activation of early signals upon CTLA-4 engagement, we found that CTLA-4 specifically up-regulates cell motility and suppresses prolonged accumulation of Talin at the contact area with antigen presenting cells upon antigen stimulation. These results suggest that Rap-1 is activated upon CTLA-4 ligation and mediates inhibitory signals through prevention of IS formation.
细胞毒性T淋巴细胞抗原4（CTLA-4）是一种T细胞共刺激受体，激活后可传递抑制性信号。CTLA-4的这种抑制作用需要小GTP酶Rap-1的激活。然而，这些负性信号背后的确切机制仍不清楚。在此，我们表明CTLA-4诱导的白细胞介素-2产生的抑制与小鼠正常T细胞克隆中免疫突触（IS）形成的快速不稳定相关。Spa-1是一种Rap-1特异性GTP酶激活蛋白（GAP），其过表达消除了CTLA-4诱导的Rap-1激活和白细胞介素-2抑制。尽管我们未能发现CTLA-4结合后对早期信号激活有任何特异性抑制，但我们发现CTLA-4在抗原刺激后特异性上调细胞运动性，并抑制Talin在与抗原呈递细胞接触区域的长时间积累。这些结果表明，Rap-1在CTLA-4连接后被激活，并通过防止IS形成介导抑制性信号。
