LFA-I-mediated regulation of immune response by Rapl.

Rapl 介导的 LFA-I 介导的免疫反应调节。

• 批准号: 12670302
• 负责人: KATAGIRI Koko
• 金额: $ 1.98万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670302/
• 关键词: LFA-1; Rap1; T cell-APC interaction; IL-2; AICD; Anergy; TCR triggering; Adhesion

Activation of T cells by antigen requires adhesive interactions with antigen-presenting cells (APC) in which LFA-1 and ICAMs are important in this process. However, it is not well understood what signaling molecules regulate this process and how modulation of adhesive events influence T cell activation. Here we show that Rap1 is activated in T cells in an antigen-dependent manner and accumulated at the contact site of T cell and antigen-loaded APC. Inhibition of Rap1 activation by a dominant negative Rap1 or SPA-1, a Rap1 GTPase activating protein, abrogates LFA-1/ICAM-1 mediated adhesive interactions with antigen-pulsed APC, and the subsequent TCR triggering and IL-2 production. Conversely, augmented antigen-dependent Rap1 activation by the expression of wild type Rap1 enhances these responses, but culminates in apoptosis by Fas/FasL. Thus, Rap1 functions as a key regulator of T cell and APC interactions and modulates T cell-responses from productive activation to activation-induced cell death by regulating the strength of adhesive interactions. Moreover, constitutive Rap1 activation rendered T cells unresponsive with accumulation of p27^<Kip1>. Our study indicates that the activation state of Rap1 has a decisive effect on the T cell-response to antigen.

抗原激活T细胞需要与抗原呈递细胞（APC）黏附相互作用，其中LFA-1和icam在这一过程中起重要作用。然而，目前尚不清楚是什么信号分子调节了这一过程，以及粘附事件的调节如何影响T细胞的激活。在这里，我们发现Rap1在T细胞中以抗原依赖的方式被激活，并在T细胞和抗原负载APC的接触部位积累。Rap1显性阴性Rap1或Rap1 GTPase激活蛋白SPA-1抑制Rap1激活，可消除LFA-1/ICAM-1介导的与抗原脉冲APC的粘附相互作用，以及随后的TCR触发和IL-2产生。相反，通过野生型Rap1的表达增强抗原依赖性Rap1激活可以增强这些反应，但最终导致Fas/FasL导致细胞凋亡。因此，Rap1作为T细胞和APC相互作用的关键调节剂，通过调节粘附相互作用的强度，调节T细胞从生产激活到激活诱导的细胞死亡的反应。此外，组成型Rap1激活使T细胞对p27^<Kip1>的积累无反应。我们的研究表明，Rap1的激活状态对T细胞对抗原的反应有决定性的影响。

项目成果

Suga, K., Katagiri, K., Kinashi, T., Harazaki, T., Iizuka, T., Hattori, M. and Minato, N.: "CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of Rap1"FEBS letters. 489. 249-253 (2001)

Suga, K.、Katagiri, K.、Kinashi, T.、Harazaki, T.、Iizuka, T.、Hattori, M. 和 Minato, N.：“CD98 通过激活诱导淋巴细胞中 LFA-1 介导的细胞粘附

Satomi Nadanaka: "Occurrence of digosialic acids on integrin α5 subunit and their involvement in cell adhesion to fibronectin"The Journal of Biological Chemistry. 276. 33657-38664 (2001)

Satomi Nadanaka：“整合素 α5 亚基上地高辛酸的出现及其参与细胞粘附到纤连蛋白”生物化学杂志 276. 33657-38664 (2001)

Koko Katagiri: "Rap1 is a potent activation signal for LFA-1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase"Molecular and Cellular Biology. 20. 1956-1969 (2000)

Koko Katagiri：“Rap1 是 LFA-1 的有效激活信号，不同于蛋白激酶 C 和磷脂酰肌醇-3-OH 激酶”《分子和细胞生物学》。

Tatsuo Kinashi: "Distinct mechanisms of α5B1 intergrin activation by Ha-Ras and R-ras"Journal of Biological Chemistry. 275. 22590-22596 (2000)

Tatsuo Kinashi：“Ha-Ras 和 R-ras 激活 α5B1 整合素的不同机制”生物化学杂志 275. 22590-22596 (2000)。

Nadanaka, S., Sato, C., Kitajima, K., Katagiri, K., Irie, S. and T. Yamagata: "Occurrence of oligosialic acids on integrinα5 subunit and their involvement in cell adhesion to fibronectin"J. Biol. Chem.. 276. 33657-33664 (2001)

Nadanaka, S.、Sato, C.、Kitajima, K.、Katagiri, K.、Irie, S. 和 T. Yamagata：“寡唾液酸在整合素 α5 亚基上的出现及其参与细胞与纤连蛋白的粘附”J。化学..276.33657-33664(2001)