Fukumoto Risaku, Dundr Miroslav, Nicot Christophe, Adams Anthony, Valeri Valerio W, Samelson Lawrence E, Franchini Genoveffa
Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH, Bethesda, MD 20892-5065, USA.
J Virol. 2007 Sep;81(17):9088-99. doi: 10.1128/JVI.02703-06. Epub 2007 Jun 20.
The p12(I) protein of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a small oncoprotein that increases calcium release following protein kinase C activation by phorbol myristate acetate, and importantly, this effect is linker for activation of T cells (LAT) independent. Here, we demonstrate that p12(I) inhibits the phosphorylation of LAT, Vav, and phospholipase C-gamma 1 and decreases NFAT (nuclear factor of activated T cells) activation upon engagement of the T-cell receptor (TCR) with anti-CD3 antibody. Furthermore, we demonstrate that p12(I) localizes to membrane lipid rafts and, upon engagement of the TCR, relocalizes to the interface between T cells and antigen-presenting cells, defined as the immunological synapse. A p12(I) knockout molecular clone of HTLV-1 expresses more virus upon antigen stimulation than the isogenic wild type, suggesting that, by decreasing T-cell responsiveness, p12(I) curtails viral expression. Thus, p12(I) has contrasting effects on TCR signaling: it down-regulates TCR in a LAT-dependent manner on one hand, and on the other, it increases calcium release in a LAT-independent manner. The negative regulation of T-cell activation by p12(I) may have evolved to minimize immune recognition of infected CD4(+) T cells, to impair the function of infected cytotoxic CD8(+) T cells, and to favor viral persistence in the infected host.
人类嗜T淋巴细胞病毒1型（HTLV-1）的p12（I）蛋白是一种小的癌蛋白，它在佛波酯肉豆蔻酸酯激活蛋白激酶C后增加钙释放，重要的是，这种效应不依赖于T细胞激活连接蛋白（LAT）。在此，我们证明p12（I）抑制LAT、Vav和磷脂酶C-γ1的磷酸化，并在T细胞受体（TCR）与抗CD3抗体结合时降低活化T细胞核因子（NFAT）的激活。此外，我们证明p12（I）定位于膜脂筏，并且在TCR结合后，重新定位于T细胞与抗原呈递细胞之间的界面，即免疫突触。HTLV-1的p12（I）基因敲除分子克隆在抗原刺激下比同基因野生型表达更多病毒，这表明p12（I）通过降低T细胞反应性来减少病毒表达。因此，p12（I）对TCR信号传导有相反的作用：一方面它以LAT依赖的方式下调TCR，另一方面，它以LAT不依赖的方式增加钙释放。p12（I）对T细胞激活的负调节可能已经进化，以尽量减少感染的CD4（+）T细胞的免疫识别，损害感染的细胞毒性CD8（+）T细胞的功能，并有利于病毒在感染宿主中的持续存在。
