Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy.
Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy.
复制标题
DOI：
10.1002/eji.200636542
复制
发表时间：
2007-04
影响因子：
5.4
通讯作者：
Muller, Ingrid
中科院分区：
文献类型：
--
作者：
Kropf, Pascale;Baud, David;Marshall, Sara E;Munder, Markus;Mosley, Angelina;Fuentes, Jose M;Bangham, Charles R M;Taylor, Graham P;Herath, Shanti;Choi, Beak-San;Soler, German;Teoh, Tg;Modolell, Manuel;Muller, Ingrid
怀孕期间需要对T细胞功能进行复杂的调节，以确保母婴耐受。在这里，我们揭示了一种新的途径，暂时抑制母亲的T细胞反应在不复杂的人类怀孕。结果表明，孕妇外周血中精氨酸酶活性显着升高，足月胎盘中精氨酸酶活性显著升高。高酶活性导致其底物L精氨酸的高周转率，并伴随着该氨基酸在微环境中的还原。氨基酸剥夺是淋巴细胞反应的一种调节途径，我们评估了这种增强的精氨酸酶活性对T细胞反应的影响。精氨酸酶介导的L精氨酸耗竭导致T细胞受体的主要信号链CD3ζ的下调和功能性T细胞的低反应性。重要的是，这种精氨酸酶介导的T细胞抑制是可逆的，因为抑制精氨酸酶活性或加入外源L精氨酸可以恢复CD3ζ链的表达和T细胞的增殖。因此，L-精氨酸代谢构成了一种新的生理机制，有助于在人类怀孕期间暂时抑制母亲的免疫反应。
Complex regulation of T cell functions during pregnancy is required to ensure materno-fetal tolerance. Here we reveal a novel pathway for the temporary suppression of maternal T cell responses in uncomplicated human pregnancies. Our results show that arginase activity is significantly increased in the peripheral blood of pregnant women and remarkably high arginase activities are expressed in term placentae. High enzymatic activity results in high turnover of its substrate l-arginine and concomitant reduction of this amino acid in the microenvironment. Amino acid deprivation is emerging as a regulatory pathway of lymphocyte responses and we assessed the consequences of this enhanced arginase activity on T cell responses. Arginase-mediated l-arginine depletion induces down-regulation of CD3ζ, the main signalling chain of the TCR, and functional T cell hyporesponsiveness. Importantly, this arginase-mediated T cell suppression was reversible, as inhibition of arginase activity or addition of exogenous l-arginine restored CD3ζ chain expression and T cell proliferation. Thus, l-arginine metabolism constitutes a novel physiological mechanism contributing to the temporary suppression of the maternal immune response during human pregnancy.