Fas and Fas ligand are critical regulators of lymphocyte homeostasis. Disruption of this pathway in the spontaneous mouse mutant gld leads to autoimmunity characterized by the appearance of a population of CD48B220+ T cells and the production of autoantibodies. Nur77 is a transcription factor that is induced upon TCR signaling. Constitutive thymic expression of Nur77 leads to apoptosis. We have previously shown that introduction of this Nur77 transgene can eliminate the accumulation of abnormal T cells in the periphery of gld/gld mice. In this report, we further characterized the effects of the Nur77 transgene on the gld phenotype. Nur77-mediated apoptosis is evident in the thymuses of mice with either a gld/gld homozygous or gld/+ heterozygous background. Consequently, few mature T cells are generated in these mice. In addition, mature T cells exhibit a diminished response to proliferative signals through CD3. Interestingly, the Nur77 transgene failed to reduce serum levels of Igs and anti-DNA Abs to wild-type levels. These data suggest that the rescue of the T cell lymphoproliferative syndrome in gld/gld mice by the Nur77 transgene is mediated by events in the thymus and that B cell autoimmune disease associated with the gld mutation can develop independently of the T cell abnormality.

The process of programmed cell death or apoptosis plays a central role in regulating lymphocyte development and homeostasis in mammals (reviewed in Refs. 1–5). Recently, many receptor/ligand pairs and effector molecules of apoptosis have been identified. While the exact roles of many of these “death receptors” and their ligands in regulating lymphocyte apoptosis have not been established, the Fas/Fas ligand (FasL)4 and TNF p75 receptor/TNF-α pairs have been shown to be critical for mature lymphocyte apoptosis. The Fas and TNF receptors (p55 and p75) are members of the TNF/nerve growth factor (NGF) receptor superfamily that share homology in their extracellular domains. Fas, TNF p55 receptor, and the recently identified DR3 (6), DR4 (7), and DR5 (8, 9) also contain an intracellular motif called the “death domain,” which is responsible for transducing the death signal. Their ligands (e.g., TNF, FasL, etc.) are members of the TNF superfamily and can exist as type II membrane proteins or as soluble cytokines the trimeric forms of which bind and activate the respective receptors. Spontaneous mutations in the Fas (lpr) and FasL (gld) genes have been identified in mice. The lpr and gld mice exhibit massive lymphoproliferation and autoimmunity characterized by the accumulation of CD483+B220+ (DN) T cells in the peripheral lymphoid organs, high serum titers of Igs, and the production of autoantibodies (10). Thus, Fas and FasL are required for peripheral lymphocyte homeostasis.

The orphan steroid receptor Nur77 was originally identified as an immediate early gene transiently induced by serum, growth factors, and NGF (for review, see 11 . We and others later found Nur77 and one of its family members, Nor-1, to be activated to a high level during TCR-mediated apoptosis. Dominant negative Nur77 can block apoptosis in T cell hybridomas as well as negative selection in transgenic mice (11). Moreover, when Nur77 or Nor-1 was introduced into thymocytes as a transgene, it induced massive apoptosis in the thymus (12, 13). Thus, Nur77 is involved in regulating thymocyte apoptosis.

The exact mechanism by which Nur77 causes apoptosis in T cells is still unclear, although it most likely involves transcriptional activation of downstream genes. Expression of Nur77 in the absence of any steroid can activate transcription through a Nur77 binding site (14, 15). Some reports have suggested that Nur77 initiates apoptosis by inducing expression of FasL, and hence it acts upstream of the Fas/FasL death pathway (13). We investigated this possibility by crossing the full length Nur77 transgenic mice to C3H/HeJ gld/gld mice. Our previous studies showed that the introduction of the Nur77 transgene eliminated the accumulation of DN T cells in the periphery of gld/gld mice, arguing that Nur77 and Fas/FasL induce apoptosis via distinct pathways (16). In the present report, we have investigated in detail the mechanism by which Nur77 rescues the T cell defect in gld/gld mice.

Genotyping of the wild-type and gld FasL alleles as well as the Nur77 transgene was performed by PCR as described previously (16).

Concentrations of serum Igs and anti-dsDNA Ab were determined by standard ELISA. For serum Igs, 96-well flat-bottom plates were coated with 10 μg/ml of the respective goat anti-mouse Ig isotype (Caltag, Burlingame, CA) in PBS at 4°C overnight. Plates were washed and then blocked with 0.5% BSA, 0.5% Tween 20 in PBS for 2 h at room temperature. After washing, dilutions of the serum samples were added and incubated overnight at 4°C. Serum dilutions were made at 1:10,000, 1:30,000, 1:90,000, and 1:270,000. After washing, goat anti-mouse Ig Ab conjugated to horseradish peroxidase were added, incubated for 5 to 10 h, and washed away thoroughly. The developing solution is prepared by mixing a 1:1 ratio of CA buffer (0.1 M citric acid; 0.1 M sodium citrate; 1.6 mg/ml of o-phenyldiamine, pH9.6) and a 1% solution of hydrogen peroxide. Measurements were made at 405 nm using a microplate reader from Bio-Rad (Hercules, CA). The actual concentrations of serum samples were determined by inclusion of a standard with every ELISA plate. A 1:2 titration of IgG (Caltag) starting at 1 μg/ml to 2 ng/ml was used to construct the standard curve.

For serum anti-dsDNA Ab, the serum samples were diluted at 1:500, 1:1,000, 1:2,000, 1:4,000, 1:8,000, and 1:16,000 and applied to 96-well plates coated with 10 μg/ml of dsDNA (Sigma, St. Louis, MO) in PBS. After washing, the samples were incubated with goat anti-mouse Ig coupled to horseradish peroxidase. Development and readout of ELISA was performed as described above. The dilution factor at which it gives an optical reading of 0.13 at 405 nm was chosen to be the unit number of anti-dsDNA titers in the samples because 0.13 falls on the midrange of the linear curve.

Lymph node lymphocytes were enriched for CD4+ T cells. The cells were incubated on a goat anti-mouse IgM-coated plate (100 μg/ml) for 30 min at room temperature. The nonadherent cells were then incubated with a biotinylated anti-Thy1.2 Ab (Caltag). Cells were washed and streptavidin-conjugated magnetic beads were added. The cells were positively selected for Thy1.2+ cells on a magnetically activated cell sorting (MACS) column (Miltenyi Biotec, Sunnyvale, CA) as per the manufacturer’s protocol. The resulting populations were consistently 85 to 95% Thy1.2+ T cells. For T cell activation, 1 × 105 cells per well were stimulated with various dilutions of plate-bound anti-CD3 Ab, with or without 10 μg/ml of anti-CD28 Ab. After 48 h, 1 μCi of [3H]thymidine was added to each sample, and the cells were incubated for an additional 16 to 20 h. Cells were harvested and incorporated 3H was counted.

We have previously shown that constitutive expression of the wild-type Nur77 transgene (Nur77FL) in gld/gld mice (hereafter referred to as Nur77FL gld/gld mice) completely eliminated the CD4CD8CD3+B220+ (DN) T cells that are characteristic of lpr and gld mice (16). This elimination of the mature DN T cells was accompanied by a dramatic reduction of splenomegaly in Nur77FL gld/gld mice (Fig. 1). Elimination of the T cell phenotype associated with the gld mutation in the Nur77FL gld/gld mouse can be due to efficient thymic deletion mediated by the Nur77 transgene that abolishes all of the DN progenitors. Alternatively, the transgene could lead to deletion of the DN T cells in the periphery. To distinguish between these possibilities, we first examined the thymic cellularity of the Nur77 transgenic mice. As described previously (12, 16), constitutive expression of Nur77 in the C57BL/6 thymus leads to apoptosis. The extent of apoptosis, however, differs between transgenic lines. In particular, Nur77FL line 12 (Tg12) has a more severe phenotype than Nur77FL line 5 (Tg5, Figure 2). We thus crossed line 12 mice to C3H/HeJ gld/gld mice. C3H/HeJ gld/gld mice were chosen over C57BL6 gld/gld because the corresponding Fas mutation has a less severe phenotype in the C57BL6 background (17). Surprisingly, when line 12 mice were crossed to C3H/HeJ-gld/gld mice, the decrease in thymic cellularity was much less severe (Tg12 gld/+, Fig. 2). The Nur77 transgene caused a similar decrease of thymic cellularity in both heterozygous gld/+ and homozygous gld/gld background (Fig. 2; and data not shown for older mice), indicating that Nur77 can initiate apoptosis in the absence of FasL in the thymus. These data also raise the possibility that genes that are polymorphic between C3H/HeJ and C57BL/6 influence the extent of Nur77-initiated apoptosis. The influence of background genes on Nur77-mediated apoptosis may have led others to conclude that Nur77 mediates apoptosis through FasL, because a comparison was made between Nur77FL (presumably in the original background) and Nur77FL gld/gld mice in the C3H/HeJ background (13).

FIGURE 1.

Rescue of splenomegaly by the Nur77 transgene (tg) in gld mice. Spleens of mice of the four different genotypes were weighed and plotted against the age of each mouse. One point represents one mouse.

FIGURE 1.

Rescue of splenomegaly by the Nur77 transgene (tg) in gld mice. Spleens of mice of the four different genotypes were weighed and plotted against the age of each mouse. One point represents one mouse.

Close modal
FIGURE 2.

Thymocytes number of Nur77 transgenic mice in C3H/HeJ and C57BL/6 background. Thymocytes from 4- to 7-wk-old mice were counted. Each circle represent one mouse (in the C57BL/6 background, n = 9 for Tg12, n = 17 for Tg5, n = 21 for the wild-type littermates (non-Tg). In the C3H/HeJ background, n = 15 for Nur77FL gld/gld, n = 4 for Nur77FL gld/+, n = 9 for gld/gld, and n = 5 for gld/+).

FIGURE 2.

Thymocytes number of Nur77 transgenic mice in C3H/HeJ and C57BL/6 background. Thymocytes from 4- to 7-wk-old mice were counted. Each circle represent one mouse (in the C57BL/6 background, n = 9 for Tg12, n = 17 for Tg5, n = 21 for the wild-type littermates (non-Tg). In the C3H/HeJ background, n = 15 for Nur77FL gld/gld, n = 4 for Nur77FL gld/+, n = 9 for gld/gld, and n = 5 for gld/+).

Close modal

Although the decrease of thymic cellularity due to Nur77 is less severe in the C3H/HeJ background, transgenic thymocytes still undergo extensive apoptosis. We performed TUNEL staining on thymocytes cultured for 3 h at either 4°C or 37°C. As shown in Figure 3, thymocytes from the Nur77FL gld/gld mice had a significant proportion of cells that were apoptotic (9.3%) compared with gld/gld (1.8%) and gld/+ (1.9%, data not shown) mice. When the thymocytes were cultured at 37°C for 3 h, the difference becomes even more prominent. Thirty-one percent of the Nur77FL transgenic thymocytes undergo apoptosis, while only 12.9% are TUNEL-positive in thymocytes from nontransgenic littermates (Fig. 3). Nur77-mediated apoptosis is also reflected in abnormal thymocyte FACS profiles (Fig. 4,A). Although the percentages of double-positive (DP for CD4/+CD8/+) and SP (CD4+CD8 and CD4CD8+) T cells in Nur77FL gld/+ and Nur77FL gld/gld mice appear normal, mature T cells do not express high levels of CD3 (Fig. 4,A). Nur77FLtransgenic thymocytes also contain a higher percentage of CD4CD8 cells. However, this translates into a similar absolute cell number of CD4CD8 T cells between transgenic and nontransgenic thymocytes (Table I). These data suggest that Nur77-mediated apoptosis occurs in the DP stage, resulting in a reduced absolute cell number of DP and SP T cells (Table I).

FIGURE 3.

Increased spontaneous apoptosis in the Nur77FL gld/gld thymocytes. Thymocytes isolated from gld/gld or Nur77FL gld/gld mice were incubated at 4°C (left) or 37°C (right) for 3 h before they were stained for TUNEL. The TUNEL-positive cells are denoted by the horizontal bar, and the percentages are shown above it.

FIGURE 3.

Increased spontaneous apoptosis in the Nur77FL gld/gld thymocytes. Thymocytes isolated from gld/gld or Nur77FL gld/gld mice were incubated at 4°C (left) or 37°C (right) for 3 h before they were stained for TUNEL. The TUNEL-positive cells are denoted by the horizontal bar, and the percentages are shown above it.

Close modal
FIGURE 4.

Thymic (A) or spleen (B) FACS profile of 4- to 7-wk-old gld/+, Nur77FL gld/+, gld/gld, and Nur77FL gld/gld mice. Numbers represent the percentage of cells in each quadrant. A, CD3 histograms show the expression of CD3 for single-positive CD4 and CD8 cells only.

FIGURE 4.

Thymic (A) or spleen (B) FACS profile of 4- to 7-wk-old gld/+, Nur77FL gld/+, gld/gld, and Nur77FL gld/gld mice. Numbers represent the percentage of cells in each quadrant. A, CD3 histograms show the expression of CD3 for single-positive CD4 and CD8 cells only.

Close modal
Table I.

Thymic cell numbers

CD4CD8CD4+CD8+CD4+CD8CD4CD8+
     
gld/+ 0.548 ± 0.074 × 107 19.93 ± 5.25 × 107 1.81 ± 0.558 × 107 0.437 ± 0.117 × 107 
(n = 6)     
gld/+, Nur77FL 0.395 ± 0.18 × 107 8.29 ± 3.088 × 107 0.82 ± 0.337 × 107 0.14 ± 0.072 × 107 
(n = 4)     
gld/gld 0.473 ± 0.121 × 107 17.85 ± 10.08 × 107 1.313 ± 0.567 × 107 0.434 ± 0.113 × 107 
(n = 7)     
gld/gld, Nur77FL 0.343 ± 0.082 × 107 7.363 ± 4.0 × 107 0.712 ± 0.359 × 107 0.118 ± 0.044 × 107
(n = 15)     
CD4CD8CD4+CD8+CD4+CD8CD4CD8+
     
gld/+ 0.548 ± 0.074 × 107 19.93 ± 5.25 × 107 1.81 ± 0.558 × 107 0.437 ± 0.117 × 107 
(n = 6)     
gld/+, Nur77FL 0.395 ± 0.18 × 107 8.29 ± 3.088 × 107 0.82 ± 0.337 × 107 0.14 ± 0.072 × 107 
(n = 4)     
gld/gld 0.473 ± 0.121 × 107 17.85 ± 10.08 × 107 1.313 ± 0.567 × 107 0.434 ± 0.113 × 107 
(n = 7)     
gld/gld, Nur77FL 0.343 ± 0.082 × 107 7.363 ± 4.0 × 107 0.712 ± 0.359 × 107 0.118 ± 0.044 × 107
(n = 15)     

We next sought to investigate whether the Nur77 transgene affects the T lymphocyte profile in the periphery. Splenocytes from 4- to 7-wk-old mice were examined for the expression of CD4, CD8, and CD3 (Fig. 4,B). As expected from the thymus results, there was a sharp decline in the number of CD4+ and CD8+ T cells in the spleen (Table II). A similar profile was observed in the lymph nodes (data not shown). Strikingly, the CD3high T cells present in nontransgenic splenocytes (gld/+, gld/gld) were greatly reduced in the transgenic splenocytes (Nur77FL gld/+, Nur77FL gld/gld), similar to that of single-positive transgenic thymocytes.

Table II.

Splenic cell numbers

CD4+CD8CD4CD8+
gld/gld (n = 5) 1.052 ± 0.257 × 107 0.431 ± 0.266 × 107 
gld/gld, Tg (n = 5) 0.223 ± 0.094 × 107 0.037 ± 0.015 × 107 
CD4+CD8CD4CD8+
gld/gld (n = 5) 1.052 ± 0.257 × 107 0.431 ± 0.266 × 107 
gld/gld, Tg (n = 5) 0.223 ± 0.094 × 107 0.037 ± 0.015 × 107 

The decreased CD3 expression may alter T cell function and therefore contribute to the rescue of T cell abnormality in gld mice. Purified CD4+ lymph node T cells from 4- to 6-wk-old mice were challenged with anti-CD28 and/or anti-CD3 Ab, and the cells were assayed for [3H]thymidine uptake 48 h later. As shown in Figure 5, CD4+ T cells from Nur77FL gld/gld mice were capable of proliferation upon stimulation with anti-CD3 and anti-CD28 Abs. However, they consistently had less response to these Abs than did their nontransgenic counterparts. The difference was especially pronounced at low concentrations of anti-CD3 Ab. Therefore, the decreased CD3 level on the Nur77FL gld/gld T cells renders the cells less capable of proliferation and expansion at limiting doses of stimulation. Alternatively, these cells may be more susceptible to apoptosis in response to suboptimal level of activation. This diminished response may account, in part, for the rescue of T cell lymphoproliferation in these mice.

FIGURE 5.

Proliferation of CD4+ T lymphocytes by anti-CD3/CD28. CD4+ T cells from gld/gld mice (open symbols) or Nur77FL gld/gld mice (closed symbols) were incubated with various concentrations of plate-bound anti-CD3 alone (circles) or anti-CD3 plus anti-CD28 (rectangles). Incorporated [3H]thymidine was plotted against the dilutions of anti-CD3 used (×10−4). The average cpm and the error bars are shown for triplicates. The results are representative of three independent experiments.

FIGURE 5.

Proliferation of CD4+ T lymphocytes by anti-CD3/CD28. CD4+ T cells from gld/gld mice (open symbols) or Nur77FL gld/gld mice (closed symbols) were incubated with various concentrations of plate-bound anti-CD3 alone (circles) or anti-CD3 plus anti-CD28 (rectangles). Incorporated [3H]thymidine was plotted against the dilutions of anti-CD3 used (×10−4). The average cpm and the error bars are shown for triplicates. The results are representative of three independent experiments.

Close modal

A hallmark of the lpr and gld mice is the production of abnormally high titers of serum Igs and autoantibodies. To investigate whether the presence of the Nur77 transgene in the T cell compartment also corrects the B cell autoimmunity in gld mice, we compared serum Ig levels and anti-dsDNA Ab in Nur77FL gld/gld mice. As shown in Figure 6,A, although the serum Ig levels of Nur77FL gld/gld mice were generally lower than in the gld/gld mice, they were consistently higher than in the gld/+ mice. The serum IgG2a and IgM levels of Nur77FL gld/gld mice in particular were higher than in the wild-type mice. Moreover, anti-dsDNA IgM Ab in Nur77FL gld/gld mice was elevated similarly as in gld/gld mice (Fig. 6,B). The anti-dsDNA IgG titers were close to wild-type level for both Nur77 gld/gld and gld/gld mice (Fig. 6 B), as has been reported by other groups (18). Thus, the Nur77 transgene expressed in T cells rescues the T cell but not the B cell autoimmunity problem in gld/gld mice.

FIGURE 6.

Serum Ig levels and autoantibody production in Nur77FL gld/gld mice are elevated. Serum Ig levels (A) and anti-dsDNA Ab levels (B) of gld/gld mice (triangles), Nur77FL gld/gld mice (diamonds), and gld/+ mice (circles) of 6- to 7-mo-old mice are determined by standard ELISA.

FIGURE 6.

Serum Ig levels and autoantibody production in Nur77FL gld/gld mice are elevated. Serum Ig levels (A) and anti-dsDNA Ab levels (B) of gld/gld mice (triangles), Nur77FL gld/gld mice (diamonds), and gld/+ mice (circles) of 6- to 7-mo-old mice are determined by standard ELISA.

Close modal

Our previous results have shown that the Nur77 transgene can eliminate the accumulation of CD483+B220+Thy-1+ (DN) T cells found in C3H/HeJ gld/gld mice (16). A key question about this phenomenon is whether this rescue of the T cell phenotype is mediated through deletion of T cells by the transgene in the thymus or in the periphery. We have shown previously that the Nur77 transgene can induce massive apoptosis in the thymus in the C57BL/6 background (12). Surprisingly, the reduction in thymocyte number was much less severe in the C3H/HeJ background. However, there are clear signs of extensive apoptosis, as indicated by the increased percentages of TUNEL-positive thymocytes and the reduction of absolute cell number of DP and SP thymocytes. Examination of the TCR Vβ usage in the transgenic T cells revealed no difference from the nontransgenic cells (data not shown). This result rules out the possibility that Nur77 eliminates a particular population of T cells that eventually gives rise to the DN T cells, which is in agreement with previous reports that no particular Vβ T cell subsets were critical for the development of DN T cells in lpr mice (19). The effect of the Nur77 transgene in the thymus is a reduction of mature T cells in 4- to 6-wk-old mice. The mature transgenic T cells are capable of proliferation in response to signals through the TCR/CD3 complex. However, their response seems to be much more sluggish than that of their wild-type counterparts, probably due to the reduced levels of TCR. While we cannot rule out the possibility that mature transgenic T cells die through apoptosis upon stimulation of the TCR/CD3 complex, we think this less likely to be the case because we cannot detect expression of the Nur77 protein in mature T cells (our unpublished data). This is consistent with the fact that the transgene is driven by the lck proximal promoter, which is active predominantly in the thymus. Furthermore, activation-induced T cell death is thought to result from the hyperactivation of the TCR/CD3 complex. A reduced CD3 expression level on the surface of mature T cells would suggest that a weaker signal is delivered to these cells. In agreement with this view, our preliminary data on TUNEL staining of peripheral T cells revealed little apoptotic cells in the transgenic lymphocytes (data not shown). Taken together, these data suggest that thymic deletion is the main contributory factor to the rescue of the DN T cell phenotype in Nur77FL gld/gld mice.

The Nur77FL gld/gld mouse still exhibits elevated levels of serum Igs and anti-dsDNA IgM Ab, showing that the Nur77 transgene can correct the T cell phenotype but not the B cell abnormality in gld mice. Others have also reported that restriction of T cell repertoire or CD8+ T cells can correct T cell but not B cell autoimmunity of lpr and gld mice (18, 20). These data are in contrast to the results obtained by several groups, showing that the lpr B cell phenotype can be corrected completely by restricting the TCR repertoire or by introducing a normal Fas transgene into the T cell compartment (21, 22, 23). The latter position would argue that manifestation of the B cell defect in lpr mice is completely dependent on T cells (24). Recent evidence that activated B cells express Fas but not FasL, however, would support the notion that a rescue of T cell abnormality would not completely abrogate the B cell problem. In this scenario, the death signal to autoreactive B cells is provided by activated T cells, which express FasL (25, 26). In transgenic lpr mice in which the T cell problem has been corrected by restricting the T cell repertoire or by introducing a wild-type Fas into the T cell compartment, a diminished expression of Fas on activated B cells due to a leaky lpr mutation may still provide an adequate signal for autoreactive B cells to die. In regular lpr/lpr mice, however, the dysregulated T cells may “expose” the apoptosis defect in B cells by raising the threshold for Fas-mediated apoptosis. One possible way by which dysregulated T cell function could affect B cell apoptosis is through cytokines. In fact, human pediatric patients with Fas mutations were shown to exhibit a skewed, Th2-like cytokine profile (27). This skewed Th2 cytokine profile is absent in parents that carry the same Fas mutations but are otherwise phenotypically normal with no manifestation of autoimmunity. Thus, whether autoimmunity will develop in lpr and gld mice may depend on both Fas/FasL interaction and cytokine regulation.

We thank Barbara Calnan for initiating the project; Peter Schow for flow cytometry; Fan Shen, Herb Kasler, and Andrea DeYoung for critical reading of this manuscript; and the Keck Foundation for purchase of a flow cytometry machine. We also thank the members of the Winoto laboratory for insightful discussion and advice.

1

This work is supported by Grant RO1 CA66236 from the National Institutes of Health, by the California Tobacco-Related Disease Research Program and by a National Science Foundation Presidential Faculty Fellow Award (to A.W.).

4

Abbreviations used in this paper: FasL, Fas ligand; NGF, nerve growth factor; DN, double negative; DP, double positive; TUNEL, TdT-mediated dUTP-X nick end labeling.

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