Adachi M, Suematsu S, Suda T, Watanabe D, Fukuyama H, Ogasawara J, Tanaka T, Yoshida N, Nagata S
Osaka Bioscience Institute, Japan.
Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2131-6. doi: 10.1073/pnas.93.5.2131.
Fas is a 45-kDa membrane protein that transduces an apoptotic signal. The mouse lymphoproliferation (lpr) mutation is a leaky mutation of Fas. In this study, we examined lymphocyte development in Fas-null mice generated by gene targeting. The Fas-/- mice progressively accumulated abnormal T cells (Thy1+, B220+, CD4-, and CD8-) and developed lymphadenopathy and splenomegaly, which were much more accelerated and pronounced than those in lpr mice. In addition, the Fas-null mice showed lymphocytosis, accompanied by lymphocytic infiltration in the lungs and liver. The number of apparently normal B cells also increased, and large amounts of immunoglobulins, including anti-DNA antibodies, were produced. Thymic clonal deletion, assessed by deletion of T cells reactive to mouse endogenous superantigens, was apparently normal in the Fas-/- mice, whereas the peripheral clonal deletion of mature T cells against a bacterial superantigen was impaired. These results suggested that Fas plays a decisive role in peripheral clonal deletion but not in negative selection in the thymus.
Fas是一种45千道尔顿的膜蛋白，可转导凋亡信号。小鼠淋巴细胞增殖（lpr）突变是Fas的一种渗漏突变。在本研究中，我们检测了通过基因打靶产生的Fas基因敲除小鼠的淋巴细胞发育情况。Fas - / -小鼠逐渐积累异常T细胞（Thy1 +、B220 +、CD4 -和CD8 -），并出现淋巴结病和脾肿大，其发展速度比lpr小鼠更快且更明显。此外，Fas基因敲除小鼠出现淋巴细胞增多症，并伴有肺和肝的淋巴细胞浸润。明显正常的B细胞数量也增加，并产生了大量免疫球蛋白，包括抗DNA抗体。通过对小鼠内源性超抗原反应性T细胞的缺失来评估胸腺克隆清除，在Fas - / -小鼠中明显正常，而成熟T细胞针对细菌超抗原的外周克隆清除受损。这些结果表明，Fas在胸腺外周克隆清除中起决定性作用，但在胸腺阴性选择中不起作用。
