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-Galactosylceramide Administration Results in Expansion of NK T Cells and Alleviates Inflammatory Dermatitis in MRL-lpr/lpr Mice 1
* Autoimmunity and Tolerance Laboratory, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267;
Gwen Knapp Center, University of Chicago, Chicago, IL 60637; and
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
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Abstract |
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14-J18 TCR -chain recognize glycolipid Ags such as -galactosylceramide (-GalCer) presented by the MHC class I-like molecule CD1d. Upon activation by -GalCer, invariant NKT cells secrete multiple cytokines and confer protection in certain immune-mediated disorders. Here we have investigated the role of NKT cells in the development of inflammatory dermatitis in MRL-lpr/lpr mice, which shares features with lupus in humans. Our results show that the numbers Sand functions of NKT (TCR
+CD1d/-GalCer tetramer+) cells, particularly of the NK1.1- subset, are reduced in MRL-lpr/lpr mice compared with MRL-fas/fas and/or nonautoimmune C3H/Hej and BALB/c mice. Repeated treatments with -GalCer result in the expansion of NKT cells and alleviate dermatitis in MRL-lpr/lpr mice. Our results indicate that NKT cell deficiency can be corrected by repeated -GalCer treatment and that NKT cells may play a protective role in inflammatory dermatitis of lupus-prone mice. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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NK T (NKT) cells represent a unique subset of immune cells that generally coexpress T cell and NK cell markers, including an invariant V14J18 TCR -chain and NK1.1 (5). Such invariant NKT cells, upon TCR engagement, promptly produce large amounts of various cytokines (5, 6). These cells recognize glycolipid Ags, such as the sea sponge-derived agent -galactosylceramide (-GalCer), in the context of the MHC class I-like molecule CD1d (5, 6). Recent studies have suggested a protective role for these cells in certain immune-mediated diseases (6, 7, 8, 9, 10, 11). In C57BL/6-lpr mice, a selective reduction in these cells precedes the development of autoimmune disease, and depletion of NK1.1+ cells (NK and NKT cells) by treatment with an anti-NK1.1 Ab accelerates autoimmunity (12). MRL-lpr mice also exhibit a decrease in the expression of V14 TCR mRNA of NKT cells before the onset of autoimmune disease (13). Consistent with a protective role for NKT cells in autoimmunity, patients with SLE and related autoimmune diseases also have a selective reduction of NKT cells (14, 15, 16, 17).
Here we have evaluated the changes in the NKT cell population in MRL-lpr mice, using specific reagents for identifying these cells ex vivo. We found that the numbers and functions of CD1d/-GalCer tetramer+ NKT cells are reduced in MRL-lpr mice compared with MRL-fas/fas (MRL-fas) and nonautoimmune C3H/Hej and BALB/c strains. In addition, we demonstrate that repeated -GalCer treatment results in the expansion of these cells, which is associated with a reduction in the frequency and severity of inflammatory dermatitis in MRL-lpr mice. Our findings suggest that it is possible to correct the NKT cell deficiency that occurs in a variety of immunological conditions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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BALB/c, C3H/Hej, MRL-fas, and MRL-lpr mice were purchased from The Jackson Laboratory (Bar Harbor, ME).
Flow cytometry
Liver lymphocytes were isolated as previously described (18). Single-cell suspensions from thymus, spleen, and lymph nodes and isolated liver lymphocytes were incubated with anti-CD16/32 (2.4G2; BD PharMingen, San Diego, CA) to block FcR
II/III, followed by staining with various conjugated mAbs (all from BD PharMingen), as indicated in the figure legends. CD1d/-GalCer tetramers were generated as previously described (19). Stained cells were analyzed using a FACSCalibur (BD Biosciences, Mountain View, CA) flow cytometer and CellQuest software.
Detection of cytokines by ELISA and cytokine secretion assay
Spleen cells (1–2 x 106/ml) were stimulated with synthetic -GalCer (20) (provided by Kirin Brewery Co., Gunma, Japan), plate-bound anti-CD3 mAb (1–10 µg/ml), or Con A (1–5 µg/ml) for 48 h. The supernatants were tested for cytokines by ELISA using mAb pairs and recombinant standards from BD PharMingen as previously described (21). To examine the cellular source of cytokines in response to -GalCer stimulation, a cytokine secretion assay was performed using the MACS Cytokine Secretion Assay Kit (Miltenyi Biotec, Auburn, CA) as previously described (18). Briefly, stimulated or control spleen cells (1 x 107) were incubated at 37°C for 45 min with the cytokine Catch Reagent, which attaches to all leukocytes via CD45 Ag and binds to the specific cytokine. After washing, cells were stained with PE-conjugated cytokine detection Ab, followed by incubation with anti-PE microbeads. Cytokine-secreting cells were then positively selected using AutoMACS (Miltenyi Biotec). Cells enriched for cytokine secretion thus obtained were counterstained with CD1d/-GalCer tetramer and anti-NK1.1 and/or anti-TCR Abs and analyzed by flow cytometry. Dead cells and B cells, which can nonspecifically bind to cytokine detection Ab via PE, were excluded by staining with propidium iodide and PerCP-conjugated B220 (BD PharMingen), respectively.
-GalCer treatment
Mice were treated i.p. with vehicle alone (100 µl of 0.15% polysorbate-20 in PBS) or with 6 µg of -GalCer (20) dissolved in vehicle, twice a week. Animals were monitored for skin and renal disease and for lymphoid enlargement, and were sacrificed at the end of treatment to harvest organs.
Assessment of dermatitis
MRL-lpr mice develop inflammatory skin lesions on the forehead, ears, and dorsum of the neck (3, 4), which were scored on a scale of 0–3, where 0 = no visible skin changes; 1 = minimal hair loss with redness and a few scattered lesions; 2 = redness, scabbing, and hair loss with a small area of involvement; and 3 = ulcerations with an extensive area of involvement. For histology, skin biopsies from the back of the neck were stored in 4% paraformaldehyde, and sectioned. The H&E-stained sections were independently scored by three of us (R.R.S., J.Y., and V.S.) for cellular infiltration (score 0–3), epidermal hyperplasia (score, 0–2), and epidermal ulcerations (score, 0–2). Results are expressed as the average of total scores from all readers.
Assessment of nephritis
Proteinuria was measured on a 0–4+ scale using a colorimetric assay strip for albumin (Albustix; Bayer, Elkhart, IN) as previously described (22). Kidney sections stained with H&E, periodic acid-Schiff, and Masson’s Trichrome were scored for the active and chronic kidney lesions (glomerular cellularity and necrosis, glomerulosclerosis, interstitial infiltration, tubular atrophy, interstitial fibrosis, and vasculitis), and the mean individual scores were summed to obtain a composite kidney biopsy score as previously described (18).
Detection of anti-DNA Ab
IgG anti-dsDNA Ab were measured by ELISA as previously described (22) and are expressed as units per milliliter using a reference-positive standard of pooled serum.
Statistical analysis
Levels of Abs and cytokines, lymphocyte percentages and numbers, and renal scores were compared using InState software (GraphPad, San Diego, CA). Student’s t test was used if the data followed a normal distribution; otherwise, a Mann-Whitney U test was used. ANOVA with Bonferroni correction was used for multiple comparisons (Fig. 1). Frequencies of Abs and proteinuria were compared using a two-sided Fisher exact test.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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A decrease in NKT cells is a common feature of autoimmune diseases (13, 14, 15, 16, 17). To specifically determine the number of NKT (V14+) cells in genetically lupus-prone mice, we enumerated TCR+CD1d/-GalCer tetramer+ cells in thymus, spleen, liver, and lymph nodes of MRL-lpr mice, MRL-fas mice that lack the faslpr mutation, normal C3H/Hej mice that have the same H2 haplotype (H2k) as MRL strains, and normal BALB/c mice. At a stage before the onset of disease (5–6 wk of age), the percentage and total tetramer+ cells in thymus and spleen were markedly reduced in MRL-lpr mice compared with age-matched MRL-fas, C3H/Hej, and BALB/c mice (Fig. 1A). The percentage of tetramer+ cells was also lower in mesenteric lymph nodes and livers of MRL-lpr mice compared with normal BALB/c and/or C3H/Hej strains (Fig. 1A), although the yields of total lymphocytes, and therefore absolute NKT cell numbers, varied considerably in lymph nodes and livers from different animals. At a stage after the onset of disease (3 mo of age), the percentage and total numbers of thymic and percent splenic tetramer+ cells continued to be lower in MRL-lpr mice than in MRL-fas, C3H/Hej, and BALB/c mice (p < 0.05 to p < 0.01; data not shown). MRL-fas mice that develop mild lupus-like disease also had reduced tetramer+ cell percentages compared with normal C3H/Hej and/or BALB/c mice at 5–6 wk and 3 mo of age (p < 0.05 to p < 0.01; Fig. 1A and data not shown). These findings suggest that the decrease in NKT cells is a feature of lupus-prone mice.
We then examined the functions of NKT cells in autoimmune-prone mice. First, we stimulated spleen cells from 5- to 6-wk-old, 3-mo-old, 5- to 6-mo-old, or 6.5- to 8-mo-old female MRL-lpr mice and the three control strains with -GalCer and tested supernatants for cytokines (n = 5–12 mice/age group/mouse strain). Essentially similar results were obtained in all age groups. -GalCer generally stimulated strong IFN-, IL-2, and IL-4 responses in normal mice, whereas the responses of all three cytokines tested were markedly reduced in MRL-lpr mice (Fig. 1B and data not shown). It is noteworthy that -GalCer-stimulated spleen cells secreted 40- to 1000-fold less IFN-, 10- to 40-fold less IL-2, and 3- to 60-fold less IL-4 in MRL-lpr mice than in control animals (Fig. 1B), while splenic NKT cell numbers were only 
3- to 5-fold lower in MRL-lpr mice than in other strains (Fig. 1A). Second, we examined the in vivo NKT cell cytokine responses to -GalCer, for which spleen cells were harvested from animals 2 h after an -GalCer injection and were stained for IFN-, IL-2, and IL-4 using a cytokine secretion assay (Fig. 1C, left panel). We found that IL-2, IL-4, or IFN--secreting tetramer+ cells were markedly decreased in MRL-lpr mice compared with MRL-fas (Fig. 1C) and BALB/c (data not shown) mice. Note that only 18% (0.11 of 0.61) of tetramer+ cells in MRL-lpr mice compared with 75% (1.82 of 2.44) in MRL-fas mice secreted IFN-; IL-2-secreting tetramer+ cells were 1 vs 32%, and IL-4 secreting tetramer+ cells were 6 vs 70% in MRL-lpr vs MRL-fas mice. Thus, the remaining NKT cells in MRL-lpr mice appear to have a functional defect in their cytokine production. These differences between MRL-lpr and control mice were better visualized by enriching the cytokine-secreting cells and analyzing the enriched cytokine+ cells for tetramer and TCR staining (Fig. 1C, right panel). The reduced NKT cell cytokine responses were not due to generalized immune suppression in MRL-lpr mice, because conventional T cells from these animals produced IFN- and IL-4 levels similar to those in non-lupus-prone mice (Fig. 1D). As expected (23), IL-2 production was lower in MRL-lpr and MRL-fas mice than in BALB/c or C3H/Hej mice. Third, we evaluated the expression of activation markers on spleen cells in response to in vitro NKT cell activation by -GalCer (Table I). Upon -GalCer stimulation, CD25 and CD69 expression increased on spleen cells by 2.2- and 8.4-fold, respectively, in BALB/c mice, but did not increase at all in MRL-lpr mice; CD86 expression increased on B cells by 18.4-fold in BALB/c vs 7.3-fold in MRL-lpr mice.
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and IL-4 production by conventional T cells, upon in vitro anti-CD3 stimulation, was unaffected in MRL strains compared with healthy strains (Fig. 1D), NKT cell IFN- and IL-4 production was dramatically reduced in MRL-lpr mice (Fig. 1B). These observations suggest that the decreased cytokine responses to -GalCer stimulation reflect a selective impairment in NKT cell function in MRL-lpr mice.
Repeated treatment with -GalCer results in the expansion of NKT cells
A number of studies have shown that within 6–12 h of activation with -GalCer or anti-CD3, NKT cells become undetectable (7, 19, 24, 25), presumably due to activation-induced cell death (25). Recent evidence, however, suggests that after a single -GalCer injection in C57BL/6 mice, NKT cell numbers recover to baseline at 24–48 h (24), further increase by 2–3 days, and remain slightly elevated at 7 days (26). We observed a similar trend in MRL-lpr mice; TCR+tetramer+ cell numbers were similar in the treated and control animals 3 days after a single injection of -GalCer (Table II).
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-GalCer in animal models of immune-mediated diseases (6, 7, 8, 9, 10, 11), little is known about the effects of such regimens on the dynamics of the NKT cell population. To address this, we asked whether repeated administration of -GalCer will expand NKT cell numbers and correct NKT cell deficiency in MRL-lpr mice. Young MRL-lpr mice were injected i.p. twice a week with -GalCer. Seven days after the fourth injection, NKT cell numbers were enumerated in these animals (Fig. 2 and Table II). We found that NKT cell numbers were not reduced in the treated animals. In fact, total tetramer+ cell numbers were higher in -GalCer-treated than in vehicle-injected animals (Table II). Thus, NKT cells can expand upon repeated in vivo activation in MRL-lpr mice. In MRL-fas mice, however, although the percentage and total numbers of NKT cells in the thymus and the total NKT cell numbers in the spleen were similar in treated and control animals, and the percentage of splenic NKT cells was lower in -GalCer-treated animals than in vehicle-injected controls (Table II). This suggests that some NKT cells may undergo activation-induced cell death by a Fas/Fas ligand-dependent mechanism.
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-GalCer-treated animals (p < 0.05 to p < 0.01; Fig. 2B). Since NK1.1-tetramer+ cells have been shown to secrete IL-4 and little IFN- (27), their expansion may lead to the type 2 immune deviation that can occur after -GalCer-treatment (7). Indeed, serum IgE levels were higher in -GalCer-treated MRL-lpr mice than in untreated controls (Fig. 2C). The treated animals also had a slightly lower IFN- response to Con A stimulation, although the differences were not statistically significant (p = 0.06 to p = 0.08; data not shown). Interestingly, the IL-2 response to anti-CD3 stimulation was increased in -GalCer-treated mice (Fig. 2D), which may be beneficial, since treatment with IL-2-expressing vaccinia virus has been reported to improve disease in MRL-lpr mice (23).
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-GalCer treatment on various spleen cell populations (Table II). The NK, T, B, and double-negative TCR+B220+ cell populations were not significantly different between the treated and control animals. Dendritic cells, however, were significantly increased in -GalCer-treated animals compared with vehicle-injected MRL-lpr and MRL-fas mice (Table II). Among dendritic cells, the CD1dint/low CD11c+ cells that may be involved in type 2 immune deviation (9) were particularly increased (3–5% in the control vs 7–9% in the treated animals), whereas the CD1dhigh CD11c+ cells that induce the type 1 cytokine response (9) were decreased (1.2–2 vs 0.6–0.8%) in -GalCer-treated animals. The significance of these alterations in dendritic cells in response to -GalCer treatment remains to be evaluated.
Treatment with -GalCer ameliorates lupus dermatitis
If spontaneous reductions in NKT cell numbers (Fig. 1) are relevant to the pathogenesis in MRL-lpr mice, then repeated treatments with -GalCer that can partially restore NKT cell numbers (Fig. 2) should inhibit the development of disease. To address this possibility, we treated young MRL-lpr mice with repeated i.p. injections of -GalCer and monitored them for various disease parameters (Fig. 4).
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-GalCer-treated MRL-lpr mice had markedly reduced frequency and severity of dermatitis: 9 of 16 (56%) mice in the vehicle-treated group, but only 2 of 16 (12%) in the -GalCer-treated group developed inflammatory skin disease (p = 0.02). A composite skin biopsy score was also reduced in -GalCer-treated mice (Fig. 4B). Representative skin biopsies show less severe lesions in the treated mice (Fig. 4C).
MRL-lpr mice also develop kidney disease characterized by marked inflammation in glomeruli and interstitium (28). To examine the effect of -GalCer treatment on kidney disease, we monitored mice for protein in urine and scored their kidney biopsies for various lesions. In contrast to the beneficial effect of -GalCer on skin disease, there was no effect of -GalCer treatment on the development of nephritis in these mice (Fig. 4, D and E). Similarly, CD1d deficiency in MRL-lpr mice does not affect lupus nephritis, but was shown to exacerbate lupus dermatitis in one study,
5 but not in another (29). Such differential regulation of lupus skin vs renal disease has also been found in 2-microglobulin-deficient MRL-lpr mice, which have exacerbation of dermatitis but amelioration of nephritis (29). Another such example is CD40 ligand-deficient MRL-lpr mice, which have low titers of autoantibodies and less severe renal disease, yet develop typical skin lesions (30). Treatment with -GalCer also had no significant effect on serum IgG anti-DNA Ab levels (Fig. 4F) or on the size, weight, and cellularity of spleen and lymph nodes (data not shown). These data suggest that different regulatory mechanisms might account for the various manifestations of lupus. The regulatory effect of NKT cells may be critical in controlling the local inflammation in the skin, but dispensable for the regulation of nephritis and other manifestations. It is also possible that the time point that we chose for the detection of skin disease may not be optimal for the detection of renal pathology, as MRL-lpr mice develop renal disease before the onset of skin disease. Nevertheless, the cumulative frequency of severe proteinuria was not significantly different between the treated and control animals (Fig. 4D). We have recently found that CD1d deficiency accelerates (18) and -GalCer treatment prevents the development of nephritis in the pristane-induced model of lupus (A. K. Singh, J. Q. Yang, L. Van Kaer, and R. R. Singh, manuscript in preparation). It is thus possible that the NKT cell-mediated regulatory effects on kidney disease may require intact Fas signaling, or the antiapoptotic effects of mutant Fas ligand are able to bypass the role of NKT cells in the regulation of kidney disease. Finally, the development of disease in target organs may depend on local factors that may be controlled by distinct loci and genes (31).
NKT cells may modulate autoimmunity via their regulating effects on APCs such as dendritic cell subsets (9) (Table II and data not shown). The unique APC subsets present in different organs, which may be differentially regulated by NKT cells, may contribute to the differential effect on various tissues in the MRL-lpr model. For example, Langerhans cells, the unique APC subset in the skin, infiltrate the dermis during the active and early stages of spontaneous skin lesions in humans with SLE and MRL-lpr mice (3, 32). These cells as well as macrophages and keratinocytes are activated in the skin lesions of MRL-lpr mice, as evidenced by increased expression of MHC class II Ags (3, 33). These activated APCs may contribute to the local lymphocytic infiltration (3) by TCR+ cells that are essential for the full spectrum of lupus-like disease, including nephritis, dermatitis, and autoantibody production, in MRL-lpr mice (30). Non-TCR+ cells, however, appear to selectively regulate the development of autoimmune skin disease in a CD40 ligand-dependent manner, as CD40 ligand-/-TCR-/- MRL-lpr mice develop renal disease and high levels of autoantibodies, but fail to develop skin disease (30). In contrast, CD40 ligand-/-TCR+ MRL-lpr mice develop less severe renal disease and low levels of autoantibodies, but develop typical skin lesions (30). How activated NKT cells influence the functions of CD40 ligand- or CD40-expressing non-TCR+ cells, such as TCR
+ cells or Langerhans cells, will be explored in further studies.
The percentage of NK1.1-expressing tetramer+ cells is lower in the MRL strain (Figs. 2B and 3) than in C57BL/6 (19, 26) and (NZB/NZW)F1 mice (our unpublished observations). The mechanism of this reduction in NK1.1 expression in MRL NKT cells remains to be determined. Recent reports have described a gradual increase in thymic NK1.1-expressing tetramer+ cells from 25% at 2 wk of age to 40% at 3 wk and 80% at 6 wk of age in C57BL/6 mice (34, 35). When extrapolating these observations to our data, it appears that NKT cells in MRL mice may have suffered a developmental arrest. Another possibility is that upon activation, NKT cells lose NK1.1 expression (26, 36). Thus, decreased NK1.1 expression in MRL-lpr mice may result from continual activation of these cells by self-glycolipid ligands.
Repeated administration of -GalCer prevents organ-specific autoimmune diseases such as type 1 diabetes (6, 7, 8, 9) and experimental autoimmune encephalomyelitis (10, 11). Prior studies have shown that NKT cells are eliminated within hours of in vivo activation (19, 25). Therefore, it is unclear whether the beneficial effect is actually mediated through NKT cells. Recent evidence suggests, however, that NKT cells, upon in vivo activation with a single -GalCer injection, quickly recover to baseline in C57BL/6 (24, 26) and MRL-lpr mice (Table II) and even expand 3–7 days after injection in C57BL/6 mice (26). In the latter study, while activated NKT cells exhibited a sustained down-regulation of the NK1.1 marker and a transient surface down-modulation of TCR-chain, the numbers of the genomic V14J18 rearrangements were unaffected (26). Thus, surface phenotypic alterations following NKT cell activation may provide an explanation for the failure of prior studies to detect NKT cell expansion in vivo. Here we demonstrate that repeated -GalCer treatment, in fact, results in a significant expansion of splenic NKT cells (Fig. 2A and Table IIA). However, the finding that repeated -GalCer injections induces expansion of NKT cells in MRL-lpr mice, but not in other strains (in fact, typically some depletion is seen; Table II), indicates that at least some activated NKT cells undergo activation-induced cell death by a Fas/Fas ligand-dependent mechanism.
Interestingly, we found that repeated -GalCer treatment results in a significant expansion of the NK1.1- subset of NKT cells (Fig. 2B). MRL-lpr mice are particularly deficient in this (NK1.1-) NKT cell population (Fig. 3) that preferentially secretes type 2 cytokines (27, 34, 35). Expansion of this NKT cell population might induce Th2 bias, as demonstrated by increased serum IgE levels in -GalCer-treated MRL-lpr mice (Fig. 2C). An increase in CD1dlow/int dendritic cells in -GalCer-treated mice may also contribute to the Th2 bias. Such type 2 immune deviation may be beneficial in MRL-lpr mice, as they produce more Th1 cytokine IFN- than all other lupus-prone and normal strains that we have tested (28). Additionally, -GalCer treatment can restore the impaired IL-2 production in MRL-lpr mice (Fig. 2D), which may also be beneficial in these mice (23).
In conclusion, NKT cells may play a regulatory role in the development of a systemic autoimmune disease, lupus dermatitis. Since humans with lupus and other systemic autoimmune diseases have reduced numbers of NKT cellsn and lupus disease activity appears to inversely correlate with circulating NKT cell numbers (15, 16, 17), therapies aimed at the in vivo activation of NKT cells might help to control dermatitis and other pathologies in patients with these diseases. Additionally, our finding that NKT cells are capable of expansion after repeated in vivo activation may have implications for designing NKT cell-based therapies for chronic immunological diseases.
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Acknowledgments |
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-GalCer. |
Footnotes |
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2 J.-Q.Y. and V.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ram Raj Singh, MSB Room 7464, 231 Albert Sabin Way, Cincinnati, OH 45267-0563. E-mail address: singhrm{at}email.uc.edu
4 Abbreviations used in this paper: SLE, systemic lupus erythematosus; -GalCer, -galactosylceramide; MRL-fas, MRL-fas/fas; MRL-lpr, MRL-lpr/lpr; NKT cells, NK T cells.
5 J. Yang, T. Chun, H. Liu, S. Hong, L. Van Kaer, C. Wang, and R. R. Singh. CD1d-deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice. Submitted for publication.
Received for publication April 21, 2003. Accepted for publication August 4, 2003.
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300 mg/dl) at different time points after treatment initiation. E, The composite kidney biopsy score (KBS; see Materials and Methods) is shown as the mean ± SE. F, Serum IgG anti-dsDNA Ab levels at different time points after treatment initiation are expressed as the mean ± SE.