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Cells in Accelerated, But Not Spontaneous, Diabetes in Nonobese Diabetic Mice1
* St. Vincent’s Institute of Medical Research, Fitzroy, Australia,
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and
Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research Center, Faculty of Medicine, University of Calgary, Alberta, Canada
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Abstract |
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cell death in type 1 diabetes. cells do not constitutively express Fas but it is induced by cytokines. The hypothesis of this study is that Fas expression should be measurable on cells for them to be killed by this mechanism. We have previously reported that up to 5% of cells isolated from nonobese diabetic (NOD) mice are positive for Fas expression by flow cytometry using autofluorescence to identify cells. We have now found that these are not cells but contaminating dendritic cells, macrophages, and B lymphocytes. In contrast cells isolated from NODscid mice that are recipients of T lymphocytes from diabetic NOD mice express Fas 18–25 days after adoptive transfer but before development of diabetes. Fas expression on cells was also observed in BDC2.5, 8.3, and 4.1 TCR-transgenic models of diabetes in which diabetes occurs more rapidly than in unmodified NOD mice. In conclusion, Fas is observed on cells in models of diabetes in which rapid cell destruction occurs. Its expression is likely to reflect differences in the intraislet cytokine environment compared with the spontaneous model and may indicate a role for this pathway in cell destruction in rapidly progressive models. |
Introduction |
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cells are destroyed by the contents of the cytolytic granules of CD8+T cells, by soluble cytokines or free radicals released by inflammatory cells within the islet lesion, or by molecules that interact with death receptors such as Fas or receptors for TRAIL (1, 2, 3, 4, 5, 6). Nonobese diabetic (NODlpr/lpr)3 mice that lack functional Fas expression do not develop insulitis or diabetes either spontaneously or following diabetogenic T cell adoptive transfer (2, 3, 7). Similarly injection of neutralizing anti-Fas ligand (FasL) protects young NOD mice from diabetes (7). Whether protection is due to effects on the interaction between T cells and islets or on interactions only between cells of the immune system remains uncertain. Human and mouse cells do not constitutively express Fas on their surface (8, 9) but it can be induced by IL-1 in humans (1) and by IL-1 or TNF in combination with IFN-
in mice (8, 10, 11). Fas expression was detected on cells in pancreatic sections from patients with type 1 diabetes (1, 12). Fas expression on islet cells of prediabetic NOD mice was reported to be detected after transfer of a diabetogenic CD8+ T cell clone (2). Also using immunohistochemistry, Suarez-Pinzon et al. (13) reported Fas expression on cells from syngeneic islets grafted into diabetic NOD mice.
The functional role of FasL in cell destruction in type 1 diabetes remains controversial. The studies performed in NODlpr/lpr mice have been questioned because of its dysfunctional immune system. Fas-deficient islet grafts from NODlpr/lpr mice were only marginally protected when transplanted into diabetic NOD mice (14). Shortly after, Kim et al. (15) reported similar findings and both studies suggested a minor role for Fas in type 1 diabetes. Furthermore, the Fas/FasL pathway had little consequence in two transgenic models of diabetes, the rat insulin promoter-influenza hemagglutinin-transgenic model (16) and the TNF-
/CD80-transgenic model (17). On the other hand, cells from TCR-transgenic mice derived from NOD T cell clones (NOD 8.3 and 4.1) destroy cells by Fas-dependent mechanisms (8, 18) because these cells on a perforin-deficient background can kill cells but not those from lpr mice and perforin deficiency does not reduce the frequency of diabetes in these mice. Also, there is evidence that the CD4+ T cell clone YNK7.3 uses FasL to kill cells of NOD mice in adoptive transfer studies, although other mechanisms may contribute (7).
Inflammatory cells and cells are close together in islets in type 1 diabetes and using immunohistology it is difficult to be sure which cell type is positive for Fas expression. This is also a problem when gene expression profiling is done using islet mRNA. To address this, we previously studied Fas expression using flow cytometry that allows cells and inflammatory cells to be analyzed separately. We found that a small number of cells (1–5%) from infiltrated islets of 100-day NOD mice expressed Fas (11). This was surprising and cast doubt on the role of Fas in NOD diabetes given that Fas was readily detectable on cytokine-treated cells and on islet-infiltrating inflammatory cells. Our hypothesis is that if Fas is important for the pathogenesis of type 1 diabetes it should be detectable on cells isolated from mice developing diabetes. The aim of the current study was to further characterize Fas-positive cells by flow cytometry and to look for Fas expression on cells in accelerated diabetes in NOD mice.
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Materials and Methods |
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NOD/Lt and NODscid mice were bred in specific pathogen-free conditions and housed in the animal facility at the Walter and Eliza Hall Institute of Medical Research. The prevalence of diabetes of female NOD/Lt mice at the Walter and Eliza Hall Institute of Medical Research was 75–80% by 300 days of age. NOD8.3 mice expressing the TCR rearrangements of the H-2Kd-restricted, cell-reactive CD8+ T cell clone NY8.3 (19) and NOD4.1 mice (20) expressing the TCR rearrangements of the I-Ag7-restricted CD4+ T cell clone NY4.1 were provided by P.S. (University of Calgary, Alberta, Canada). BDC2.5 TCR-transgenic mice carrying a TCR transgene derived from an I-Ag7 cell-reactive CD4+ T cell clone were provided by D. Mathis and C. Benoist (Harvard University, Cambridge, MA).
Islet isolation
Islets of Langerhans were isolated from mice as previously described (21, 22). Briefly, the pancreas was perfused via the common bile duct with collagenase P (Roche Molecular Biochemicals, Indianapolis, IN) followed by purification of islets on a Histopaque-1077 gradient (Sigma-Aldrich, St. Louis, MO). For flow cytometry, islets were dispersed into single cells by a brief incubation with 0.2% trypsin (Calbiochem, San Diego, CA)/10 mM EDTA in HBSS. Dispersed islets were then washed free of trypsin and allowed to recover in CMRL 1066 medium (Life Technologies, Gaithersburg, MD) plus 10% FCS for 0.5–1 h before staining. Islet cells were usually analyzed on the day of isolation. RNA extraction from islets and RT-PCR for members of the suppressors of cytokine signaling (SOCS) family were performed as previously described (23).
Flow cytometry
After recovering, dispersed islet cells were either resuspended in balanced salt solution with 2% FCS and 1 µg/ml propidium iodide to stain dead cells for sorting by MoFlo (DAKO, Fort Collins, CO) or stained with mAbs using standard procedures. Islet cells were analyzed for expression of Fas by flow cytometry as previously described (11). Antisera used were anti-Fas (Jo2; BD PharMingen, San Diego, CA) (or hamster anti-human Bcl-2 as an isotype control) followed by biotinylated anti-hamster Ig (BD PharMingen) and PE-conjugated streptavidin. Three-color immunofluorescence was used for simultaneous staining of cells with anti-Fas and anti-CD45 (anti-leukocyte common Ag) conjugated to PerCp-Cy5.5 (3F11; BD PharMingen). Further analysis of islet cells included simultaneous staining with anti-CD45 conjugated to PE and N418, Mac-1, B220, and 145-2C11, all conjugated to biotin and followed by Tri-Color conjugated to streptavidin (Caltag Laboratories, Burlingame, CA). Where Tri-Color and PerCp-Cy5.5 were used, propidium iodide was used at 3.3 µg/ml. Analysis was performed on a FACScan (BD Biosciences, Mountain View, CA).
Immunostaining
For cytospins, 4 x 104 dispersed and sorted islet cells were spun onto silaine (Sigma-Aldrich)-coated slides. Slides were fixed in 4% paraformaldehyde at room temperature for 30 min, air dried, and stored at -20°C until required for staining. Immunofluorescence was performed using standard procedures. Blocking was with 10% FCS and 2% skim milk in PBS and antisera were incubated for 30 min with 5-min washes in PBS. Antisera used were anti-insulin (DAKO) with anti-guinea pig Ig-FITC (BD Biosciences), anti-glucagon/somatostatin (DAKO) with anti-rabbit Texas Red (Molecular Probes, Eugene, OR), and anti-CD45 (30F11; BD PharMingen) with anti-rat Ig-FITC (SILENUS Labs, Boronia, Australia). Staining was visualized by confocal microscopy.
Adoptive transfer of diabetes
Splenocytes from NOD mice with blood glucose levels above 14 mM were considered diabetic and used for adoptive transfer of diabetes into NODscid mice or NOD mice irradiated at 900 rad. Briefly, 2 x 107 donor cells, purified free of RBCs, were injected i.v. into the tail vein of recipients. Mice were monitored after 7 days for diabetes by urine and blood glucose measurements.
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Results |
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cells from freshly isolated islets or those cultured in low concentrations of glucose have high autofluorescence due to intracellular flavin adenine dinucleotide levels (24). Islets were stained and analyzed on the day of isolation. Examination of islet cells on forward scatter (size) vs autofluorescence (FL-1 channel) revealed three distinct cell populations; high (region 1), medium (region 2), and low autofluorescence (region 3) (Fig. 1A). We have previously reported that 1–5% of the region 1 cells isolated from older NOD mice are Fas positive. To determine whether these were cells or non- cells contaminating the region 1 gate, islet cells from 90- to 110-day female NOD mice were sorted according to autofluorescence, fixed onto slides, and stained by immunofluorescence for insulin, glucagon, and somatostatin (Fig. 1B). In the high autofluorescence population, the majority of cells stained for intracellular insulin. Some insulin-positive cells were also observed in region 2, the medium autofluorescence gate, and occasional insulin-positive cells appeared in region 3. Glucagon- and somatostatin-positive cells were observed in region 2, with glucagon being more common. A small number of glucagon-positive cells was observed in region 3.
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cells (25). Staining was performed on islets isolated from NOD mice at 45 days (minimal infiltrate) and 100 days (extensive infiltrate). Most of the cells in the low autofluorescence population stained for CD45 in the 45- and 100-day NOD mice (Fig. 2). The number of cells in this population also increased with the age of the NOD mice, as expected for infiltrating inflammatory cells. Some cells in the medium autofluorescence population were positive for CD45 in the 100-day mice and fewer in the 45-day mice. A very small number (5%) was positive for CD45 in the high autofluorescence group at 100 days (Fig. 2). High autofluorescence/CD45+ cells were not detected at 45 days. The number of CD45+ cells in this subgroup was similar to the number of Fas+ cells previously observed (11). To confirm the presence of CD45+ cells in the high autofluorescence population, cells sorted on the basis of autofluorescence were stained for CD45. CD45+ cells were clearly observed in the high and the medium autofluorescence populations although as expected the majority of CD45+ cells were in the low autofluorescence population (Fig. 1B).
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To ascertain whether the CD45+ cells found in the high autofluorescence region were also Fas+ and account for the Fas+ cells found in that region, islet cells were simultaneously stained with anti-CD45 and anti-Fas and analyzed by flow cytometry (Fig. 3). Strikingly, when the small proportion of CD45+ cells in the high autofluorescence population were analyzed, they were all positive for Fas staining. Similarly, all CD45+ cells in the medium autofluorescence group were Fas+. All of the low autofluorescence Fas-expressing cells were also CD45+. CD45- islet cells from NOD did not stain more with anti-Fas than CD45- islet cells from NODscid mice or from strains without autoimmune diabetes. These data indicate that the Fas+ cells found in islets isolated from NOD mice are of hemopoietic origin and islet endocrine cells do not express detectable levels of Fas under these conditions.
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Fas expression on cells in NOD mice with accelerated diabetes
We next analyzed Fas expression on cells in the more intense and accelerated form of diabetes that follows transfer of spleen cells from NOD mice with diabetes to NODscid mice and in diabetes in TCR-transgenic NOD mice. Following adoptive transfer, diabetes occurs in the recipients 20–30 days later. Islets were isolated from recipients before the development of diabetes (Fig. 4). Increased Fas expression on CD45-negative high autofluorescence cells was clearly discernible compared with the same cells from NODscid mice or from NOD mice during the evolution of spontaneous diabetes, indicating that cells were expressing Fas in this form of NOD diabetes. The fluorescence profiles indicated that Fas expression was increased on all cells.
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cells was observed in 8.3NOD mice that carry a TCR transgene (Fig. 5). Onset of insulitis has been reported to be quite variable in this model. Increased Fas expression was observed when insulitis was present and Fas expression was not observed before insulitis in any mice. As mice progressed to diabetes, which begins at 5–6 wk of age, fewer cells could be isolated but with higher Fas expression level. Similarly, cell Fas expression was also observed on cells from CD4+ NOD TCR-transgenic mice BDC2.5 and 4.1 mice before development of diabetes (Fig. 6).
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A possible reason for the lack of Fas expression on cells in spontaneous diabetes is the expression of molecules that could block Fas expression. Examples of this include the SOCS family or IL-1R antagonist. The latter has previously been shown to be expressed in NOD islets (26). We analyzed NOD islets for expression of SOCS family members by RT-PCR. SOCS-1, cytokine-inducible SH2-containing protein, and SOCS-2 were all expressed in NOD islets with SOCS-1 appearing around 70 days of age (Fig. 7).
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Discussion |
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cells makes at least some contribution to the development of diabetes. Fas can be detected on cytokine-treated cells and they are susceptible to FasL in vitro (11). To understand the significance of Fas expression, it would be helpful to be able to detect Fas expression on cells. In this study, Fas expression was undetectable on cells isolated from NOD mice during spontaneous diabetes but increased Fas expression was clearly observed on cells during accelerated diabetes caused by transfer of diabetogenic splenocytes or in several TCR-transgenic models. It remains possible that during spontaneous diabetes Fas is expressed at low levels that are functionally significant but we have found that cells isolated from NOD mice at 100 days of age are not susceptible to FasL in vitro without previous cytokine treatment (our unpublished data), indicating that Fas is expressed at levels that are also functionally undetectable. This is consistent with the minor impact of cell Fas deficiency or FasL neutralization on spontaneous diabetes (14, 15). Our demonstration of Fas expression during accelerated diabetes is consistent with previous observations of Fas expression on cells measured by immunohistology after transfer of diabetogenic T cells (2) and after transplantation of islets into diabetic NODs (13). However, flow cytometry, compared with immunohistology, allows more accurate quantitation of the number of Fas+ cells and confirmation that Fas is expressed on cells rather than infiltrating leukocytes by using a number of criteria, particularly lack of CD45 expression. These observations validate that Fas staining is not lost during islet isolation and show that if Fas expression is present on cells our methods can detect it. Flow cytometric detection of Fas is likely to be a useful readout of the effects of therapeutic interventions in experimental diabetes.
We previously reported that 
5% of cells in NOD mice express Fas (11). We now report that this was caused by approximately the same percentage contamination of the cell gate by Fas-positive leukocytes. Further analysis of the CD45-positive cells in this population showed they are likely to be dendritic cells, macrophages, and B cells. Essentially all of the CD45+ cells in the infiltrate were highly Fas-positive, indicating previous activation of the cells. Most, particularly T cells, were found in the low autofluorescence population. Once CD45+ cells were removed from analysis by gating, there was no evidence that CD45-negative cells were Fas+. These data suggest that Fas up-regulation on cells is not a feature of spontaneous autoimmune diabetes in NOD mice, unlike in humans. It is not clear whether this important difference is due to differences in the cytokines expressed in the insulitis lesion or in the way Fas is regulated in mouse and humans. NOD cells display increased levels of class I MHC protein expression (27) that is dependent on IFN- (22). IFN- alone, however, is not sufficient to increase Fas on mouse cells (although it may be on human cells) and the surprising absence of Fas up-regulation during spontaneous NOD diabetes appears to indicate that there is insufficient local effect of IL-1 and/or TNF. The data suggest that they are not present in sufficient quantity or because inhibitors of cytokine action, such as the IL-1R antagonist protein (26) or SOCS family members (this study), are present. Although it is difficult to be sure from these data that the inhibitors are expressed by cells or infiltrating cells and whether they are expressed at sufficient levels, it is plausible that they may be playing a role. The level of SOCS-1, however, is insufficient to block class I MHC expression on cells (22). They are consistent with the idea that spontaneous diabetes in NOD mice is a highly regulated process that results in a protracted course of cell destruction. Slow progression to diabetes and absence of Fas expression may both reflect similar mechanisms such as production of TGF- or IL-10, increased expression of extracellular cytokine inhibitors such as IL-1Ra, or even intracellular inhibitors such as members of the suppressors of cytokine signaling family. We were unable to detect Fas on cells from islets with early insulitis or preinsulitis despite evidence that Fas plays a role in the initiation of insulitis, particularly recent data showing that Fas neutralization early in the course of disease can prevent progression (7). While one possibility is that Fas is expressed at low levels that we have missed, another is that the role of Fas in early insulitis does not depend on its expression on cells but expression on other cell types.
In contrast, the data in accelerated diabetes show that stimuli able to up-regulate Fas must be present and that the local cytokines are either quantitatively or qualitatively different from those in spontaneous diabetes. Both IL-1 and TNF are able to increase Fas expression with IFN-; therefore, these two cytokines are candidates for molecules present in accelerated but not spontaneous diabetes. The availability of cytokine knockout mice will make it possible to sort out which molecules are important for Fas up-regulation and to address whether blockade of the factors that cause Fas up-regulation also protects against diabetes. It is likely that diabetes resulting from transfer of diabetogenic T cells is mediated primarily by perforin and granzymes, as it is in spontaneous diabetes. Fas expression may be more critical in other settings, particularly in the absence of perforin-dependent killing of cells by CTLs and we are actively exploring this possibility. The ability to measure Fas expression on cells provides an important tool to dissect mechanisms of cell cytotoxicity in models of diabetes and to indicate the potential efficacy of Fas inhibition to prevent cell destruction.
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Footnotes |
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Cell Life and Death." T.W.H.K. holds a Career Development Award and H.E.T. holds an advanced Postdoctoral Fellowship from the Juvenile Diabetes Research Foundation. P.S. is a Senior Scholar of the Alberta Heritage Foundation for Medical Research. 
2 Address correspondence and reprint requests to Dr. Thomas Kay, St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria, 3065, Australia. E-mail address: kay{at}medstv.unimelb.edu.au
3 Abbreviations used in this paper: NOD, nonobese diabetic; FasL, Fas ligand; SOCS, suppressor of cytokine signaling.
Received for publication December 30, 2002. Accepted for publication April 14, 2003.
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