Marangoni Francesco, Trifari Sara, Scaramuzza Samantha, Panaroni Cristina, Martino Silvana, Notarangelo Luigi D, Baz Zeina, Metin Ayse, Cattaneo Federica, Villa Anna, Aiuti Alessandro, Battaglia Manuela, Roncarolo Maria-Grazia, Dupré Loïc
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
J Exp Med. 2007 Feb 19;204(2):369-80. doi: 10.1084/jem.20061334. Epub 2007 Feb 12.
A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4(+)CD25(+)FOXP3(+) natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses to self-antigens and allergens. Therefore, we investigated the effect of WAS protein (WASP) deficiency on the distribution and suppressor function of nTreg cells. In WAS(-/-) mice, the steady-state distribution and phenotype of nTreg cells in the thymus and spleen were normal. However, WAS(-/-) nTreg cells engrafted poorly in immunized mice, indicating perturbed homeostasis. Moreover, WAS(-/-) nTreg cells failed to proliferate and to produce transforming growth factor beta upon T cell receptor (TCR)/CD28 triggering. WASP-dependent F-actin polarization to the site of TCR triggering might not be involved in WAS(-/-) nTreg cell defects because this process was also inefficient in wild-type (WT) nTreg cells. Compared with WT nTreg cells, WAS(-/-) nTreg cells showed reduced in vitro suppressor activity on both WT and WAS(-/-) effector T cells. Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4(+) effector T cells in vitro. Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients.
很大一部分威斯科特-奥尔德里奇综合征（WAS）患者会出现自身免疫和过敏症状。CD4(+)CD25(+)FOXP3(+)自然调节性T（nTreg）细胞在维持外周免疫耐受、防止机体对自身抗原和过敏原产生免疫反应中起关键作用。因此，我们研究了WAS蛋白（WASP）缺陷对nTreg细胞分布及抑制功能的影响。在WAS基因敲除（WAS(-/-)）小鼠中，胸腺和脾脏中nTreg细胞的稳态分布及表型均正常。然而，WAS(-/-) nTreg细胞在免疫小鼠中的植入情况较差，提示其稳态受到干扰。此外，WAS(-/-) nTreg细胞在T细胞受体（TCR）/CD28触发后无法增殖，也不能产生转化生长因子β。WASP依赖的F-肌动蛋白向TCR触发位点的极化可能与WAS(-/-) nTreg细胞缺陷无关，因为该过程在野生型（WT）nTreg细胞中也效率低下。与WT nTreg细胞相比，WAS(-/-) nTreg细胞对WT和WAS(-/-)效应T细胞的体外抑制活性均降低。同样，WAS患者外周血中nTreg细胞水平正常，但在体外无法抑制自体和异体CD4(+)效应T细胞的增殖。因此，WASP似乎在nTreg细胞的激活和抑制功能中起重要作用，nTreg细胞功能障碍或定位错误可能导致WAS患者发生自身免疫。
