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Proc Natl Acad Sci U S A. Jun 7, 2011; 108(23): 9542–9547.
Published online May 18, 2011. doi:  10.1073/pnas.1018182108
PMCID: PMC3111309
Immunology

Key role for IL-21 in experimental autoimmune uveitis

Abstract

IL-21 is a pleiotropic type 1 cytokine that shares the common cytokine receptor γ-chain, γc, with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21 is most homologous to IL-2. These cytokines are encoded by adjacent genes, but they are functionally distinct. Whereas IL-2 promotes development of regulatory T cells and confers protection from autoimmune disease, IL-21 promotes differentiation of Th17 cells and is implicated in several autoimmune diseases, including type 1 diabetes and systemic lupus erythematosus. However, the roles of IL-21 and IL-2 in CNS autoimmune diseases such as multiple sclerosis and uveitis have been controversial. Here, we generated Il21-mCherry/Il2-emGFP dual-reporter transgenic mice and showed that development of experimental autoimmune uveitis (EAU) correlated with the presence of T cells coexpressing IL-21 and IL-2 into the retina. Furthermore, Il21r−/− mice were more resistant to EAU development than wild-type mice, and adoptive transfer of Il21r−/− T cells induced much less severe EAU, underscoring the need for IL-21 in the development of this disease and suggesting that blocking IL-21/γc–signaling pathways may provide a means for controlling CNS auto-inflammatory diseases.

IL-21 is a type 1 four-α-helical-bundle cytokine with major actions on a range of lymphoid populations (1). IL-21 signals via IL-21R and the common cytokine receptor γ-chain, γc (1), which is mutated in humans with X-linked severe combined immunodeficiency (2) and is shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (3). IL-21 is produced mainly by CD4+ T cells, including Th17 cells (1, 4), T follicular helper cells (5), and natural killer (NK) T cells (6). It promotes the function and expansion of effector CD8+ T cells (7) and can activate NK cells (8). It is also critical for B-cell differentiation into plasma cells and Ig production (9, 10) and negatively regulates the function of dendritic cells (11). IL-21 plays a role in autoimmune diseases, including type I diabetes in nonobese diabetic mice (12, 13), systemic lupus erythematosus in MRL/lpr and BXSB/Yaa mice (9, 14, 15), and collagen-induced arthritis (16). In experimental allergic encephalitis (EAE), divergent effects of IL-21 have been reported related to its role in the development and progression of the autoimmune response as well as whether it is required for disease development (1, 17, 18).

The genes encoding IL-21 and IL-2 are adjacent and share similar genomic organization in humans and mice (19). Coevolution of the IL-21 and IL-2 systems is further suggested not only by their sharing of γc but also by the fact that IL-21R is most closely related to IL-2Rβ (20); nevertheless, IL-21 and IL-2 have distinct functions. For example, IL-21 is implicated in the development of autoimmunity (9, 1214, 16), but mice deficient in IL-2, IL-2Rα, and IL-2Rβ exhibit autoimmunity (2124), suggesting that IL-2 protects against development of autoimmune disease. IL-21 can promote the development of Th17 cells, whereas IL-2 inhibits the differentiation of Th17 cells (25), although it induces the expansion of Th17 cells that mediate uveitis and scleritis (26).

Uveitis is a group of sight-threatening idiopathic intraocular inflammatory diseases including Behçet's disease, birdshot retinochoroidopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada, and ocular sarcoidosis, which may be of infectious or autoimmune etiology (27). Experimental autoimmune uveitis (EAU) shares pathological features with human uveitis, and much of our understanding of the etiology and pathophysiology of this disease derives from studies of EAU (27, 28). EAU can be induced in susceptible rodent species by immunization with the retinal protein, interphotoreceptor retinoid-binding protein (IRBP) (Materials and Methods). Although the etiology of noninfectious uveitis is unknown, patients with uveitis have more IL-17–producing T cells (Th17) in peripheral blood than healthy individuals (29). Moreover, Th17 cells increase during active uveitis but decrease after treatment, suggesting that they play a role in the disease process (26). Consistent with a role for Th17 cells in CNS autoimmune diseases, mice with targeted deletion of the Stat3 gene in T cells cannot generate Th17 cells and do not develop EAU or EAE (30), indicating the importance of Th17 cells in uveitis and multiple sclerosis. Because IL-21 is produced by Th17 cells, mediates its biological actions in part via STAT3, and promotes Th17 differentiation, IL-21 could be a potential mediator of EAU.

An impediment to the study of the role of IL-21–expressing T cells in disease has been the absence of high-quality Abs for detecting in situ expression of IL-21 in tissues by intracellular staining. In this study, we generated bacterial artificial chromosome (BAC) reporter transgenic (Tg) mice in which the promoters of the adjacent Il2 and Il21 genes in a BAC clone spanning both genes direct expression of emGFP and mCherry, respectively. These mice allowed us to investigate in vivo the presence of IL-21 (mCherry) and/or IL-2 (emGFP)–expressing T cells in lymph nodes (LNs) and to monitor their infiltration into the retina during EAU. We detected a substantial increase in T cells expressing Il2-emGFP and Il21-mCherry in LNs before the onset of inflammation, and these cells were subsequently detected in the retina of mice with EAU, suggesting their involvement in the pathogenic mechanism of uveitis. We also found that Il21r−/− mice have defective development of EAU, and involvement of IL-21 in this disease was further shown by adoptive transfer experiments.

Results

Identification of IL-21– and IL-2–Expressing Cells in Vivo Using Il21-mCherry/Il2-emGFP Reporter Mice.

To evaluate IL-21 and IL-2 gene expression, we generated Il21-mCherry and Il2-emGFP BAC dual reporter Tg mice (Fig. 1A). For most experiments, we used a founder line containing one integrated copy of the reporter construct, but behavior of a second independent BAC reporter mouse line was similar (Fig. S1 A and B). To validate the reporter mice, we stimulated CD4+ T cells enriched from the Tg reporter and wild-type (WT) littermate mice with anti-CD3 and anti-CD28 and analyzed the expression of emGFP and IL-2 by flow cytometry (Fig. 1B). The frequency of IL-2+ cells determined by intracellular staining was ~35% in both Tg reporter mice and WT controls. In the reporter mice, >95% of emGFP+ cells also produced IL-2, and ~70% of IL-2–producing cells were emGFP+, even though our fixation procedure included paraformaldehyde, which can quench the emGFP fluorecence. We also stimulated CD4+ T cells with anti-CD3 + anti-CD28 and sorted emGFP and emGFP+ cells. By intracellular staining, 60% of the emGFP+ but only 11% of emGFP cells were IL-2+ (Fig. S2A). Moreover, we evaluated IL-2 and IL-21 mRNA expression of sorted emGFPmCherry double-negative (DN), emGFP+ and mCherry+ single-positive, and emGFP+mCherry+ double-positive (DP) cells by real-time PCR. mCherry+ and DP cells had ~30-fold higher IL-21 mRNA expression than DN cells. As expected, IL-21 mRNA expression in GFP+ cells was weaker. emGFP+ cells had higher IL-2 mRNA expression than DN and mCherry+ cells, and IL-2 mRNA expression of DP cells was less than in GFP+ cells but still fivefold higher than in DN cells (Fig. 1C). We also stimulated CD4+ T cells with anti-CD3 + anti-CD28 with or without IL-6 and TGF-β for 18 h and evaluated mRNA expression of mCherry, IL-21, emGFP, and IL-2 by RT-PCR. Levels of mCherry and IL-21 mRNA were highly correlated (R2 = 0.99) as were emGFP and IL-2 mRNA (R2 = 0.89) (Fig. 1D), further validating the Il2-emGFP/Il21-mCherry reporter mice.

Fig. 1.
Characterization of Il21-mCherry/Il2-emGFP reporter Tg mice. (A) Shown is a BAC containing the Il21 and Il2 genes, with mCherry and emGFP introduced. (B) Splenic CD4+ T cells from control and reporter Tg mice were stimulated with anti-CD3 + anti-CD28 ...

We next stimulated CD4+ T cells with anti-CD3 + anti-CD28 under neutral conditions (presence of anti–IFN-γ + anti–IL-4) versus Th1 or Th17 conditions and analyzed cells at days 1, 2, and 3 (Fig. 1E). emGFP as a marker for IL-2 increased under all conditions but least under Th17 conditions, whereas mCherry as a marker of IL-21 production was highest in Th17 cells. As expected, Th1 cells expressed both emGFP and mCherry, consistent with their known production of IL-21 (1) as well as of IL-2. Sorting of cells after Th1 stimulation revealed that ~28.5% of emGFP+ cells produced IFN-γ versus <2% of mGFP cells (Fig. S2B). Similarly, sorting of cells after Th17 differentiation revealed that ~11% of the mCherry+ cells produced IL-17A versus <3% of mCherry cells (Fig. S2C).

To identify IL-21– and IL-2–producing cells in vivo, we next examined Il21-mCherry/Il2-emGFP expression in liver, spleen, and other lymphoid tissues. CD4+ cells that expressed mCherry, emGFP, or both were present in all tissues examined, but the frequencies of the cell subsets differed in different tissues (Fig. 1F). Approximately 1–2% of CD4+ T cells in spleen, as well as axillary, cervical, and mesenteric LNs, were Il2-emGFP+, in contrast to ~0.5% in the liver, whereas there were more of these cells (3–4% of CD4+ T cells) in the small intestine lamina propria lymphocytes (SI LPLs) and in the colon LPLs, consistent with higher basal stimulation in the gut (Fig. 1F, Top). For Il21-mCherry, expression tended to be lowest in liver, axillary, and cervical LNs, slightly higher in spleen, mesenteric LNs, and colon, and highest (10% of cells) in SI LPLs (Middle). Cells expressing both Il2-emGFP+ and Il21-mCherry were detected in all tissues, but were highest in the gut (Bottom). Thus, Il2-emGFP+ and Il21-mCherry+ cells were present in all immune compartments examined, with relative enrichment in the intestine. Evaluation of splenic CD4+ T cells revealed that ~80% of these Il2-emGFP+ and Il21-mCherry+ cells were CD44hiCD4+ effector/memory type T cells (Fig. 1G). When we gated on CD4+CD44+mCherry+ and CD4+CD44+emGFP+ cells, 39% of Il21-mCherry+ cells and 38.6% of Il2-emGFP+ cells were both mCherry+ and emGFP+ (Fig. 1H).

Augmented Expression of IL-21 and IL-2 Expression in EAU.

We next immunized the reporter Tg mice with IRBP and examined mCherry and emGFP expression at day 21, at which point mice had developed severe uveitis. After immunization, we detected Il2-emGFP+ CD4+ T cells in draining LNs (Fig. 2 A and Left Panel of B). mCherry also increased from 2% of CD4+ T cells before immunization to ~9% afterward (Fig. 2B, Center). After immunization, ~4% of CD4+ cells were Il21-mCherry+/Il2-emGFP+ DP cells (Fig. 2B, Right). From 50,000 LN cells for each sample, mCherry+ cells increased from ~220 to ~590 cells after immunization. emGFP+ cells and DP cells increased from ~200 to ~500 and from ~90 to ~210 cells, respectively (Fig. 2C). Similar results were obtained with a second reporter BAC Tg mouse line containing six copies of the BAC clone rather than one (Fig. S1). We also sorted DN, emGFP+, mCherry+, and DP cells from CD4+-draining lymphocytes 21 d after immunization and performed both RT-PCR and intracellular staining. As expected, mCherry+ cells had high Il17a mRNA expression (Fig. 2D), consistent with IL-17A cytokine production (Fig. 2E). Ifng mRNA was expressed in emGFP+, mCherry+, and DP cells (Fig. 2D), and correspondingly, IFN-γ protein was produced by these three populations (Fig. 2E). We also examined IL-21– and IL-2–producing cells in draining LNs and retina using confocal microscopy and reporter Tg mice not immunized or immunized with IRBP. Il21-mCherry and Il2-emGFP were expressed in draining LNs at day 7 (Fig. 2F) and in the eye at day 21 after immunization (Fig. 2G). Of the emGFP+ and/or mCherry+ cells infiltrating the retina, ~50% were Il2-emGFP+, ~25% were Il21-mCherry+, and ~25% were DP cells (Fig. S3). Thus, during EAU development, expression of both IL-2 and IL-21 was induced in autoreactive CD4+ T cells, and cells expressing each cytokine as well as cells expressing both cytokines were present in the inflammatory cells infiltrating the retina.

Fig. 2.
Increased Il2-emGFP and Il21-mCherry expression after EAU induction (A and B) Expression of Il2-emGFP and Il21-mCherry in draining lymphocytes from reporter Tg mice 21 d after immunization with IRBP, gated on CD4+ cells. Shown are representative mice ...

Less Severe EAU in Il21r−/− Mice.

Given the role of IL-21 in the development of autoimmune diseases and its expression within the retina, we investigated the development of EAU in WT versus Il21r−/− mice, monitoring by fundoscopy from day 10 after immunization to the end of the study period (approximately day 25). Compared with the normal control (Fig. 3A, Left), WT retinas at day 21 showed severe inflammation with blurring of the optic disk margins, retinal vasculitis with cuffing (red asterisks), and inflammatory infiltrates (black arrows) (Fig. 3A, Center). Histological analysis revealed massive inflammatory cell infiltration in the vitreous (black arrows), photoreceptor cell damage and retinal folds (Fig. 3B, blue arrows), and choroiditis (Fig. 3B, Center panels). In contrast, Il21r−/− mice had modest fundoscopic changes, with less inflammation, only slight retinal vasculitis with cuffing (red asterisk) (Fig. 3A, Right), and less severe histological changes (Fig. 3B, Right panels). EAU scores based on fundoscopy (31) (Fig. 3C) or histology (32) (Fig. 3D) showed much less disease in the Il21r−/− mice. Correspondingly, at day 21, the proliferation of draining LN cells from EAU WT mice was greater than in unimmunized animals in response to IRBP (Fig. 3E). Proliferation was induced by immunization with IRBP in Il21r−/− mice but was lower than in WT mice (Fig. 3E). IL-17–expressing and IFN-γ–expressing T cells have been implicated in EAU (26). We therefore examined the production of IL-2, IL-17, and IFN-γ from CD4+ T cells in peripheral blood mononuclear cells (PBMCs) after EAU induction. There was significantly less IL-17 and IFN-γ production in Il21r−/− mice, but IL-2 production was similar in WT and Il21r−/− mice (Fig. 3 F and G). Moreover, when draining LN cells were harvested at day 21 and then stimulated with IRBP for 3 d, there was less IL-17A and IL-1β but more IL-10 production in Il21r−/− mice (Fig. 3H). IL-6 production tended to be lower, but the difference was not significant (Fig. 3H). Overall, these data indicate a possible shift from pro- to anti-inflammatory cytokines in the absence of IL-21 signaling.

Fig. 3.
Loss of IL-21 signaling protects mice from EAU. (A) Fundus images from C57BL/6 WT mouse (Left) and WT or Il21r−/− mice 20 d postimmunization with IRBP (Center and Right). Red asterisks, retinal vasculitis with cuffing; black arrows, inflammatory ...

Adoptive Transfer of IRBP-Specific Uveitogenic Lymphocytes from Il21r−/− Mice Induces Less Severe EAU than WT Cells.

To confirm that the Il21r−/− mouse defect occurred in the generation of IRBP-specific pathogenic T cells, we adoptively transferred WT and Il21r−/− IRBP-specific lymphocytes into WT mice. We found similar CD3 and CD4/CD8 profiles (Fig. 4A, Left and Center panels), but the Il21r−/− cells produced less IL-17A and IFN-γ but similar levels of IL-2 (Fig. 4A). Compared with mice receiving WT cells, animals receiving Il21r−/− cells exhibited less severe EAU as evaluated by fundoscopy (Fig. 4B), histological analysis (Fig. 4C), and clinical EAU score (Fig. 4D).

Fig. 4.
Il21r−/− mice are defective in generating IRBP-specific pathogenic T cells. Draining LN cells from WT and Il21r−/− EAU mice were stimulated with IRBP for 4 d and then adoptively transferred into C57BL/6 WT mice. (A) WT ...

Discussion

In this study, we investigated the role of IL-21 in EAU development. The expression of IL-21 in draining LNs and retina, as revealed by the Il21-mCherry/Il2-emGFP reporter mice; the diminished development of EAU in I l21r−/− mice; and the less severe EAU following adoptive transfer of IRBP-specific lymphocytes from Il21r−/− mice together underscore the importance of IL-21 in the development of EAU. WT mice mounted a higher IL-17 response than did Il21r−/− mice. Given that IL-21 can promote Th17 cell differentiation (1), it is possible that the lack of IL-21 signaling protects mice from EAU through a mechanism involving decreased production of IL-17, which has been suggested to be important for the development of both EAU (26, 29) and EAE (17). Previously, IL-21 was shown to play important roles in animal models of type 1 diabetes (12, 13) and systemic lupus erythematosus (14, 15). Our data now implicate this cytokine in a model of autoimmunity causing disease at an immunologically “privileged” site as well, revealing its very broad contribution to autoimmunity.

By analyzing the location of Il21-mCherry+ and Il2-emGFP+ cells after inducing EAU, we infer that immunization by IRBP caused an immune response that produced both IL-21 and IL-2 in draining LNs, and both IL-21– and IL-2–producing cells were located in the eye at day 21, when severe inflammation is evident. Previously, IL-2 was reported to enhance protection from EAU in part by stimulating production of anti-inflammatory cytokines by regulatory T cells (33). The ability of IL-2 to inhibit Th17 differentiation (25) is another mechanism by which IL-2 might inhibit EAU. The fact that there were both IL-2– and IL-21–expressing cells in the inflammatory neuroretina in EAU is interesting, as both overlapping and distinctive actions for these cytokines have been noted (1, 34). Interestingly, IL-2 can expand Th17 cells once developed, potentially promoting uveitis and scleritis (26), and Daclizumab, a monoclonal antibody to IL-2Rα, can control inflammation in patients with noninfectious uveitis (35, 36), suggesting a role for IL-2 in the pathogenesis of this disease. Our data showing the presence of IL-2/IL-21 double-producer T cells in EAU extend these data.

In summary, we have shown a key role of IL-21 in the development of EAU, suggesting that interfering with the action of this cytokine may have therapeutic potential for uveitis. Moreover, we have generated Il21-mCherry/Il2-emGFP double reporter Tg mice to help study the role of IL-2 and IL-21 in the pathogenesis of EAU. These mice may be valuable for studying the potential roles for IL-2 and IL-21 in a broad range of other disease models as well.

Materials and Methods

Mice.

Il21r−/− mice (10) were produced by breeding heterozygous mice. C57BL/6 mice were from the Jackson Laboratory. To generate Il2-emGFP/Il21-mCherry Tg reporter mice, we used the RP23-98I15 BAC clone (Invitrogen), which contains the Il21 and Il2 genes (Fig. 1A). Recombineering (37) was used to introduce the emGFP (Invitrogen) and mCherry (38) coding sequences linked to the SV40 poly(A) site into the first exon of the Il2 and Il21 genes, respectively. Recombineering comprises a two-step method to create precise genetic changes: first, amp-sacB is placed in the DNA and then this is replaced with the emGFP or mCherry coding sequences in a second recombineering event. The targeting cassettes with amp-sacB were amplified using primers with ≥50 bp 5′ overhangs that were homologous to the regions of the BAC just outside of the segment being replaced. The primers are provided in SI Materials and Methods. BAC clones that had integrated the targeting construct were selected, and the location of the insert was confirmed by PCR and sequencing. The BAC was prepped using a Large-Construct kit (Qiagen), digested with NotI, DNA purified by phenol/chloroform extraction, and microinjected into fertilized C57BL/6J × CBA/J oocytes. Resulting pups were screened for the emGFP and mCherry reporters by PCR (see SI Materials and Methods for the primers). Founder lines were backcrossed at least six generations to C57BL/6 mice. Experiments were performed under protocols approved by the National Eye Institute and/or National Heart, Lung, and Blood Institute Animal Care and Use Committees.

Analysis of CD4+ T-Helper Cells.

For Th1 conditions, CD4+ T cells (>98% pure) were treated with plate-bound 2 μg/mL anti-CD3 + soluble 1 μg/mL anti-CD28, 10 μg/mL anti–IL-4, and 10 ng/mL IL-12 for 3 d. For Th17 conditions, cells were treated with anti-CD3/CD28, 20 ng/mL IL-6, 2 ng/mL TGF-β1, and 10 μg/mL each of anti–IFN-γ and anti–IL-4. Cytokines and antibodies were from R & D Systems. For intracellular cytokine detection, cells were stimulated for 4 h with 10 ng/mL phorbol 2-myristate 3-acetate (PMA) + 1 μM ionomycin, Golgi-stop added in the last 2 h, and intracellular cytokine staining performed using a Cytofix/Cytoperm kit (BD Pharmingen). Flow cytometry was performed using a FACSCalibur (BD Biosciences). All mAbs were from BD PharMingen. Flow cytometry was performed on an LSRII (BD Biosciences). mCherry was detected using a 561-nm laser with a 605/40 filter.

Real-Time PCR.

mRNA was isolated from 106 cells (RNeasy mini kit; Qiagen) and cDNA was prepared (Omniscript RT kit, Qiagen). Real-time PCR was performed with an ABI PRISM 7700 sequence detection system with site-specific primers and probes (Applied Biosystems).

Induction and Evaluation of EAU.

Mice were immunized with 150 μg bovine IRBP and 300 μg human IRBP peptide (amino acids 120) in 0.2 mL 1:1 vol/vol emulsion with complete Freund's adjuvant (CFA) containing Mycobacterium tuberculosis strain H37RA (2.5 mg/mL). Mice simultaneously received 0.3 μg Bordetella pertussis toxin. Clinical disease was scored by fundoscopy (31) and histological analysis (32), as detailed in SI Materials and Methods. Tissue sections were also examined using a multiphoton laser-scanning confocal microscope with fluorescence emission detected with 515/30 (emerald-GFP, green) and 600/40 (mCherry, red), as described (26, 31). For adoptive transfer experiments, draining LN cells from WT and Il21r−/− EAU mice (at day 21) were stimulated with IRBP 20 μg/mL for 4 d, and 107 cells in 200 μL of PBS were injected i.v. into sex- and age-matched recipient mice. Fundoscopic examinations were performed 14 d after adoptive transfer.

Cytokine Analysis and Lymphocyte Proliferation Assays.

A total of 5 × 106 draining LN cells were cultured for 3 d in medium containing 10 μg/mL IRBP protein, and IL-6, IL-10, IL-1β, and IL-17 levels were measured using an ELISA kit (BD PharMingen). For proliferation, normal control and EAU draining lymphocytes (2 × 106/mL) were stimulated with 20 μg/mL IRBP. After 48 h, cultures were pulsed with [3H]thymidine (0.5 μCi/10 μl/well) and incorporation was measured 12 h later.

Statistical Analyses.

Nonparametric t tests and Prism software (Graphpad Software) were used.

Supplementary Material

Supporting Information:

Acknowledgments

We thank Dr. Robert Fariss and Mercedes Campos for help with confocal microscopy, Barbara J. Taylor for help with FACS analysis, Dr. Yunsang Lee and Yongjun Lee for help with immunization of mice and fundoscopy, and Drs. Jian-Xin Lin, Yrina Rochman, and Rosanne Spolski, National Heart, Lung, and Blood Institute, for valuable discussions and critical comments. This work was supported by the Divisions of Intramural Research, National Heart, Lung, and Blood Institute and National Eye Institute and by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (Grant 2010-0010483 to H.-P.K.).

Footnotes

Conflict of interest statement: W.J.L. is an inventor on patents and patent applications related to IL-21.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1018182108/-/DCSupplemental.

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