Enhanced and accelerated lymphoproliferation in Fas-null mice

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.