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Enhanced and Accelerated Lymphoproliferation in Fas

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Enhanced and Accelerated Lymphoproliferation in Fas Proc. Natl. Acad. Sci. USA Vol. 93, pp. 2131-2136, March 1996 Biochemistry Enhanced and accelerated lymphoproliferation in Fas-null mice MASASHI ADACHI*, SACHIKO SUEMATSUt, TAKASHI SUDA*, DAISUKE WATANABE*, HIDEHIRO FUKUYAMA*, JUN OGASAWARA*, TAKASHI TANAKAt, NOBUAKI YOSHIDAt, AND SHIGEKAZU NAGATA* *Osaka Bioscience Institute, 6-2-4 Furuedai, Suita. Osaka 565. Japan, and 'Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi, Osaka 590-0)2, Japan Communicated by Charles Weissmann, Universitat Ziurich, Zutriclh, Switzerland, November 22, 1995 (received for review Jutne 26, 1995) ABSTRACT Fas is a 45-kDa membrane protein that retrovirus-into an intron of the Fas chromosomal gene transduces an apoptotic signal. The mouse lymphoprolifera- (25-28), which results in premature termination and aberrant tion (lpr) mutation is a leaky mutation of Fas. In this study, splicing of the Fas transcript. However, a small amount of we examined lymphocyte development in Fas-null mice gen- intact Fas mRNA or protein is expressed in the thymus of lpr erated by gene targeting. The Fas-/- mice progressively mice (26, 28, 29), indicating that the lpr mutation is leaky (25). accumulated abnormal T cells (Thyll, B220+, CD4-, and Therefore, it was thought that the absence in lpr mice of altered CD8-) and developed lymphadenopathy and splenomegaly, thymic cell development was related to the leakiness of the which were much more accelerated and pronounced than mutation (29). those in lpr mice. In addition, the Fas-null mice showed To overcome this problem, we created Fas-knockout mice lymphocytosis, accompanied by lymphocytic infiltration in and found that they developed hepatomegaly in addition to the lungs and liver. The number of apparently normal B cells lymphoproliferation (30). In this study, we examined the also increased, and large amounts of immunoglobulins, in- development of lymphocytes in the Fas-null mice. The devel- cluding anti-DNA antibodies, were produced. Thymic clonal opment of lymphadenopathy and splenomegaly in the Fas-null deletion, assessed by deletion of T cells reactive to mouse mice was much sooner than that in lpr mice. In addition, these endogenous superantigens, was apparently normal in the mice showed massive lymphocytosis, which was occasionally Fas-/- mice, whereas the peripheral clonal deletion ofmature accompanied by infiltration of lymphocytes into the lungs and T cells against a bacterial superantigen was impaired. These liver. Not only abnormal T cells (Thy-I+ B220+ CD4- CD8-) results suggested that Fas plays a decisive role in peripheral but also apparently normal B and T cells accumulated in clonal deletion but not in negative selection in the thymus. Fas-/- mice, and these mice produced a large excess of immunoglobulins. Despite the enhanced abnormality in lym- During lymphocyte development, many cells die by apoptosis phocyte development, negative selection assessed by the de- at various steps. Over 95% of the precursor T cells in the letion of T cells reactive to endogenous superantigens was thymus are eliminated (1) by negative selection or by the apparently normal in Fas-/- mice, indicating that Fas may not absence of positive selection. Mature T cells also die in the be involved in this process. periphery. T cells that recognize the self antigens expressed only in the peripheral tissues, or those activated by foreign MATERIALS AND METHODS antigens for a long period, die by apoptosis (2, 3). During the development of B cells, those that fail to correctly recombine Animals. Generation of mice carrying the Fas-null mutation immunoglobulin genes are eliminated, whereas those that has been described elsewhere (30). In brief, the targeting produce autoreactive antibodies are negatively selected in the vector was constructed by replacing exon 9 of the Fas gene with bone marrow as well as in peripheral lymphoid tissues (4, 5). the neo and 13-galactosidase genes. E14-1 embryonic stem cells The Fas ligand (FasL) is a type II membrane protein with a from 129/Ola mice were disrupted by homologous recombi- mass of 40 kDa, and it is mainly expressed in activated T cells nation, injected into blastocysts isolated from C57BL/6, and (6-9). FasL binds to its receptor, Fas (also called APO-1), transferred to foster mothers to produce male chimeric mice. which is a 45-kDa type I membrane protein expressed in These were bred with C57BL/6 female mice. Mice heterozy- activated T and B cells, as well as in the liver, heart, and lungs gous for the Fas mutation (FI) were then intercrossed to (10, 11). The binding of FasL or agonistic anti-Fas antibody to generate litters (F2), which carried the wild-type (Fas+/+), Fas induces apoptosis and kills cells within hours (6, 10, 12-14). heterozygous (Fas+/-), or homozygous (Fas-/-) Fas muta- Studies in vivo and in vitro have indicated that the Fas/FasL tion. The complete loss of functional Fas in the thymocytes and system is involved in the activation-induced suicide of T cells hepatocytes of Fas-/- mice has been demonstrated (30). (15-18). Flow Cytometry, Serological, and Histological Studies. Molecular and genetic analyses of Fas and FasL have Lymphocytes were prepared from spleens and lymph nodes as indicated that mouse lymphoproliferation (lpr) and general- described (31). Lymphocytes were isolated by dissecting the ized lymphoproliferative disease (gld) are mutations of Fas and liver into small pieces, filtering them through a steel mesh (100 FasL, respectively (13, 19). These mutant mice develop lymph- gauge), and then suspending the filtrate in RPMI 1640 medium adenopathy by accumulating abnormal T cells (52) and suffer as described (32). Flow cytometry proceeded essentially as from systemic lupus erythematosus-like autoimmune disease described (24). The monoclonal antibodies used for staining (20). Peripheral clonal deletion appears to be impaired in lpr were phycoerythrin (PE)-conjugated anti-CD4 (Becton Dick- mice (18, 21). Whereas negative selection in the thymus is inson, clone GK 1.5), fluorescein isothiocyanate (FITC)- essentially normal (21-23), functional Fas is expressed in conjugated anti-CD8 (PharMingen, clone 53-6.7), PE- CD4+ CD8 thymocytes that are susceptible to positive and conjugated anti-B220 (GIBCO/BRL, clone RA3-6B2), and negative selection (24). The lpr mutation is caused by inserting FITC-conjugated anti-Thyl.2 (PharMingen, clone 30-H112). an early transposable element-namely, a mouse endogenous The following biotin-conjugated monoclonal antibodies from The publication costs of this article were defrayed in part by page charge Abbreviations: PE, phycoerythrin; FITC, fluorescein isothiocyanate; payment. This article must therefore be hereby marked "advertisenlent' in V, variable region; SEB, staphylococcal enterotoxin B; WBC, white accordance with 18 U.S.C. §1734 solely to indicate this fact. blood cell. 2131 Downloaded by guest on September 24, 2021 2132 Biochemistry: Adachi et al. Proc. Natl. Acad. Sci. USA 93 (1996) PharMingen were also used for staining in combination with RESULTS PE- or FITC-conjugated streptavidin (Becton Dickinson or GIBCO/BRL, respectively): anti-Vi35.1, -5.2 (clone MR9-4), Lymphadenopathy, Splenomegaly, and Lymphocytosis. anti-V38.1, -8.2 (clone MR5-2), and anti-Vpl1 (clone RR3-15) Like MRL-lpr mice, the lymph nodes and spleen of Fas-null antibodies (V, variable region). Two-color flow cytometry was mice became enlarged in an age-dependent manner. As shown in Fig. 1, the spleen and lymph nodes of Fas+/+ and Fas+/- performed with a FACScan (Becton Dickinson), and the data mice weighed about the same at any age. On the other hand, were analyzed with LYSIS II software. these organs of Fas-/- mice became progressively larger than The levels of serum IgM, IgGl, IgG2a, IgG2b, and IgG3 those in FasI/I mice. At 16 weeks of age, the spleen and lymph were estimated by single radial immunodiffusion with kits from nodes were about 15 and 100 times larger than those in Fas+/+ Serotec. Anti-single-stranded DNA and anti-double-stranded mice, respectively. The progression of splenomegaly and DNA antibodies were quantified as described (32) using a lymphadenopathy was more pronounced in Fas-null mice than Mesacup EIA system from MBL (Nagoya, Japan). Serum was in MRL-lpr mice (Fig. 1). Female and male Fas-null mice serially diluted with Tris-buffered saline TBS; 25 mM similarly developed lymphadenopathy and splenomegaly. The Tris HCl, pH 7.4/140 mM NaCl) and added to the microtiter total number of lymphoid cells recovered from Fas-/- mice plates. After incubation at room temperature for 30 min, was 2 x 109 from the spleen and an average 5 x 108 per lymph bound antibodies were detected with peroxidase-conjugated node. Flow cytometry indicated that 60-70% of the cells that rabbit anti-mouse IgG or IgM (Zymed) using o-phenylenedi- accumulated in the lymph nodes and spleen of the Fas-/- mice amine as a substrate. The absorbance at 492 nm was measured at age of 16 weeks were Thy-1i B220+ CD4- CD8- (Fig. 2). with an automated Micro-ELISA reader. For histological The cells expressed CD3 but not IgM (data not shown), analysis, the major organs from autopsied mice were weighed, indicating that the cells were originated from T cells. The fixed in 10% formalin, sectioned at 3 ,um, and then stained with proportions of normal T (B220- Thy-i+) in all peripheral hematoxylin and eosin. lymphoid organs and B cells (B220+ Thy-1 +) in the spleen and Clonal Deletion in the Thymus and Periphery. To study blood of Fas-/- mice were reduced. However, considering that thymic clonal deletion, F1 mice heterozygous at the Fas the total number of cells increased about 13- and 100-fold in mutation obtained by crossing 129 x C57BL/6, were back- the spleen and lymph nodes, respectively, these results crossed with MRL/Mp- + / + mice for two generations. The F3 indicated that not only abnormal CD4- CD8- T cells but heterozygous mice were intercrossed to obtain F4 homozygous also apparently normal T and B cells were abundant in mice termed F4-MRL.
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