International Immunology

International Immunology Advance Access originally published online on December 21, 2007
International Immunology 2008 20(2):209-214; doi:10.1093/intimm/dxm135

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Differential roles for IFN- and IL-17 in experimental autoimmune uveoretinitis

Takeru Yoshimura^1,2, Koh-Hei Sonoda¹, Yoshiyuki Miyazaki³, Yoichiro Iwakura⁴, Tatsuro Ishibashi¹, Akihiko Yoshimura² and Hiroki Yoshida³

¹ Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
² Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka
³ Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga
⁴ Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Correspondence to: H. Yoshida; E-mail: yoshidah{at}med.saga-u.ac.jp

	Abstract

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IL-17-producing CD4⁺ T cells, so called T_h17 cells, constitute a newly identified inflammatogenic cell population, which is critically involved in some inflammatory diseases. To explore the role of T_h17 cells in murine experimental autoimmune uveoretinitis (EAU), a model of human autoimmune uveitis where T_h1 responses predominantly participate in the pathogenesis, IL-17^–/– mice were immunized with interphotoreceptor retinoid-binding protein peptide 1–20 for disease induction. Funduscopic examination revealed that EAU was induced in IL-17^–/– mice just like in wild-type (WT) mice at early phases of the disease. However, at later/maintenance phases, the severity was significantly reduced in IL-17^–/– mice. Expression of IFN- and MCP-1 was comparable between WT and IL-17^–/– mice during the time course. In vivo blockade of IFN- and IL-4 resulted in exacerbation of EAU at later phases with augmented IL-17 production. Taken together, our data demonstrated that IL-17/T_h17 participates in the late phases of EAU and also that T_h1 and T_h17 responses are differentially required for EAU.

Keywords: autoimmunity, cytokines, inflammation, T_h1, T_h17

	Introduction

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Human endogenous uveitis, such as Vogt–Koyanagi–Harada disease and Behcet's disease, is a common sight-threatening intraocular inflammatory disease and has been extensively studied using a murine model of experimental autoimmune uveoretinitis (EAU). EAU is an organ-specific T cell-mediated autoimmune disease that can be induced by immunization with retinal antigens including interphotoreceptor retinoid-binding protein (IRBP). During EAU, the integrity of blood–retinal barrier is compromised, and monocytes/macrophages and antigen-specific T lymphocytes infiltrating into the retina cause tissue damages. It has been generally believed that EAU is caused by activation of T_h1 cells. Recently, lines of evidence suggest that newly recognized IL-17-producing CD4⁺ T cells play a crucial role in several autoimmune diseases by mediating tissue inflammation (1). These cells, termed T_h17, constitute a T_h cell lineage distinct from T_h1 and T_h2 cells. While initial differentiation of T_h17 cells requires transforming growth factor-β (TGF-β) and IL-6, IL-23 is required for their expansion or activation (2, 3). It is also known that the development of T_h17 is negatively regulated by IFN- and IL-4 (2, 4).

To delineate the in vivo role of T_h17 and IL-17 in the induction of ‘T_h1-mediated’ autoimmune diseases, we transferred IRBP-specific T_h17 cells generated in vitro into wild-type (WT) mice for induction of EAU. T_h17 cells induced EAU in the recipient mice as efficiently as T_h1 cells generated similarly. By immunization with IRBP peptide, EAU was also induced in IL-17^–/– mice just similarly to WT mice at the induction phase but the disease severity was reduced at late/maintenance phases in IL-17^–/– mice. Given the importance of T_h1 responses at the induction phase of EAU (5), our data demonstrated that IL-17/T_h17 cells are critically involved in EAU and also that T_h1 and T_h17 responses are differentially required for induction of EAU.

	Methods

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Mice
IL-17^–/– in C57BL/6 background (6) and WT C57BL/6 mice (SLC Japan, Shizuoka, Japan) were maintained in specific pathogen-free conditions at Kyushu University, Japan. All animals were treated humanely. All experiments were approved by the Institutional Animal Research Committee of Saga University (approval number 15-011-03) and conformed to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research.

EAU induction and evaluation
WT C57BL/6 and IL-17^–/– mice were immunized with human IRBP peptide 1-20 (GPTHLFQPSLVLDMAKVLLD), as described previously (7). EAU was also induced by sub-retinal transfer of cells. Briefly, lymph nodes (LNs) were removed from C57BL/6 mice 14 days after IRBP immunization. LN cells were cultured in the presence of 10 µg ml^–1 IRBP1-20 plus either 1 ng ml^–1 rIL-12 (R&D Systems, Minneapolis, MN, USA) for T_h1 differentiation, 1 ng ml^–1 recombinant IL-23 (eBioscience, San Diego, CA, USA) for T_h17 differentiation or no cytokine added for control T_h0 culture, for initial 5 days followed by another 5-day culture (Fig. 1B). CD4⁺ T cells were purified with megnetic cell sorting MACS (Myltenyi Biotec, Auburn, CA, USA; >95% purity). One million cells per 2 µl per mouse were injected into the sub-retinal space of the right eyes of WT mice using 32G needles (Hamilton, Reno, NV, USA) under microscopic guidance as described previously (5). EAU severity was assessed both clinically and histopathologically in a blind manner as described elsewhere (8, 9). For clinical scoring, funduscopic examinations of mice were performed after immunization. Tropicamide (0.5%) was applied to the eyes for mydriasis. Fundus of the eye was examined with Bonnoscope and Super Field NC Lens (Volk Optical, Mentor, OH, USA). Two ophthalmologists performed the clinical assessments in a masked fashion. The presence of vessel dilatation, vessel white focal lesions, vessel white linear lesions, retinal hemorrhaging and retinal detachment were determined. According to the severity of these findings, the EAU clinical scores were graded 0–4 as described by Thurau et al. (8) with some modifications. When two ophthalmologists had different scores, mean value was calculated as a clinical grade at that point.

View larger version (43K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. Induction of EAU by Th17 cells. (A) LN cells and ocular-infiltrating cells (Eye) from WT B6 mice were stimulated with PMA plus ionomycin and were stained for CD4, intracellular IL-17 and IFN-. Shown are representative staining data for IL-17 versus IFN- in CD4+ cells from three independent experiments. (B) Sub-retinal transfer protocols. CD4+ T cells prepared as described in Methods were transferred into sub-retinal spaces of naive WT mice (n = 5). (C and D) Th17 differentiation of IL-23-treated IRBP-specific CD4+ T cells. CD4+ T cells cultured in the presence or absence of IL-23 as shown in B were stimulated with 10 µg ml–1 IRBP along with irradiated WT splenocytes and supernatants were analyzed for IL-17 production by ELISA (C). To confirm the content of Th1 and Th17 preparations, cultured LN cells as in (B) were stimulated with PMA plus ionomycin and stained as in (A) (D). (E) EAU symptoms in the eyes were evaluated 5 days after cell transfer. The values represent mean ± SEM. *P < 0.05. (F) Eyes were examined histopathologically 5 days after cell transfer (n = 5). Inflammatory infiltrates were detected in the eyes of the naive mice transferred with IRBP-specific Th17 CD4+ T cells while no apparent infiltrates were detected in the mice receiving control IRBP-specific CD4+ T cells (Th0). Data are representative of three independent experiments. Re, retina; VC, vitreous cavity.

 
Intracellular cytokine staining
Ocular-infiltrating cells were prepared as described previously (10). Cervical, sub-mandibular and inguinal LNs were collected on indicated days after immunization. LN or ocular-infiltrating cells were stimulated for 4 h with 50 ng ml^–1 phorbol myristate acetate (PMA) and 1 µg ml^–1 ionomycin in the presence of brefeldin A (eBiosciences), then stained with anti-CD4 and fixed and permeabilized using Intracellular Fixation buffer and Permeabilization buffer (eBiosciences), followed by anti-IFN- and anti-IL-17 staining. Antibodies used for flow cytometric analysis are Fc block (anti-mouse FcR- II/III mAb, 2.4G2), PE-conjugated anti-IL-17, FITC-conjugated anti-IFN- and allophycocyanin-conjugated anti-CD4 antibodies (all from eBiosciences).

Cytokine ELISA
LNs were collected on indicated days after immunization. Single-cell suspensions were prepared and enriched for CD4⁺ T cells. Suspended CD4⁺ T cells were incubated with IRBP peptide at a concentration of 2 x 10⁵ cells per 200 µl per well for 48 h at 37°C. Irradiated (20 Gy) spleen cells from WT mice were used as antigen-presenting cells in the cultures at a concentration of 1 x 10⁶ cells per 200 µl per well. Supernatants were collected, and IFN- and IL-17 concentrations were measured using mouse ELISA development kits (eBiosciences) according to the manufacturer's instructions.

Reverse transcription–PCR analysis
Eyes were removed from mice (n = 5) on indicated days after immunization under deep anesthesia. Irises, retinas and choroids were prepared by removal of corneas and lenses from the eyes. Total RNA extracted from the eye using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) was reverse transcribed into cDNA using murine leukemia virus reverse transcriptase (Applied Biosystems, Foster City, CA, USA). First, β-actin mRNA expression was measured with quantitative real-time PCR (ABI PRISM 7000; Applied Biosystems, Tokyo, Japan) as an internal control. Equal amounts of cDNAs were amplified for expression of MCP-1 and IFN- genes. Primers used for MCP-1 and IFN- were described previously (11).

In vivo antibody treatment
For in vivo blockade of IFN- and IL-4, rat anti-mouse IFN- mAb (R4.6A2) and anti-IL-4 mAb (11B11, kindly provided by Kubo, RIKEN, Japan) were used. Rat IgG (Zymed Laboratories, South San Francisco, CA, USA) was used as a control antibody. Mice were injected intra-peritoneally with anti-IFN- and anti-IL-4 mAb or control antibody (250 µg per mouse) every other day from one day before immunization.

Statistical analysis
Unpaired Student's t-test for parametric data (cytokine production) and Mann–Whitney U-test for non-parametric data (EAU scores) were used to analyze differences between groups of mice. P < 0.05 was considered to be statistically different.

	Results

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Induction of EAU by antigen-specific CD4⁺ T_h17 cells
Until recently, it has been demonstrated that IFN- produced by antigen-specific T_h1 cells plays an essential role in the development of EAU. However, IL-17 has also been reported to contribute to some autoimmune diseases including experimental autoimmune encephalomyelitis (EAE) (12). To determine the possible involvement of IL-17 in EAU, we first examined the production of IL-17, in addition to IFN-, by ocular-infiltrating CD4⁺ T cells and draining LN after EAU induction. Fourteen days after immunization, cells from eyes or LN were stimulated with PMA/ionomycin, followed by intracellular staining for IFN- versus IL-17. As shown in Fig. 1(A), both IFN- and IL-17 were detected in the ocular-infiltrating cells and the draining LN cells. To further examine the role of IL-17 produced by CD4⁺ T cells in EAU induction, we prepared IRBP-specific T_h17 cells (Fig. 1B–D), a population known to be highly inflammatogenic in EAE (10), and sub-retinally transferred them to WT recipient mice. IRBP-specific T_h17 cells generated in the presence of IL-23 induced EAU as efficiently as T_h1 cells, when compared with T_h0 cells (Fig. 1E). Mice transferred with control T_h0 population showed 1.0 of clinical scores, which may be due to surgical intervention or to small contamination of IFN--producing cells in T_h0 population (Fig. 1D). Histological examination of the eyes revealed infiltration of lymphocytes, macrophages and neutrophils in the retina of T_h17-transferred recipient mice, just like in T_h1-transferred mice (Fig. 1F and data not shown). These data demonstrated that, in addition to T_h1 cells, IL-23-induced T_h17 cells were involved in the induction of EAU, although contribution of small number of contaminating IFN--producing cells in T_h17 population or IL-17-producing cells in T_h1 population was not completely excluded.

Contribution of IL-17 at late phases of EAU
To further examine the role of IL-17 in EAU, we induced EAU in IL-17^–/– mice by IRBP peptide immunization (Fig. 2A). From day 9 to 21, severity of EAU in IL-17^–/– mice was similar to that in WT mice. Strikingly, however, IL-17^–/– mice showed better recovery than WT mice at later phases such as on day 25 and later. Histological examination of the eyes on day 25 (Fig. 2B) revealed lower cellular infiltration in IL-17^–/– mice than in WT mice (histological score; 0.8 ± 0.3 versus 1.8 ± 0.8, P = 0.22, n = 6). On day 15 after immunization when disease scores were equivalent between WT and IL-17^–/– mice, CD4⁺ T cells from WT and IL-17^–/– mice produced almost equal amounts of IFN- while only WT CD4⁺ T cells produced substantial amounts of IL-17 (Fig. 2C). Expression of IFN- and MCP-1, representative T_h1-related genes, was also equivalent between the two groups over the time course (days 9, 15 and 25; Fig. 2D). These data clearly demonstrated that EAU was successfully induced even in the absence of IL-17. It was suggested that IL-17 was involved in EAU pathogenesis at later phases and that IL-17 was not required for the disease induction. In contrast, IFN- and T_h1 responses play a role throughout the time course of the disease.

View larger version (45K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2. Induction of EAU in IL-17–/– mice. (A) Clinical scores of EAU in IL-17–/– mice. WT B6 mice (open circles; n = 26) and IL-17–/– mice (closed circles; n = 24) were immunized with IRBP as described in Methods, and from day 9, disease severity was examined. The values represent mean ± SEM. *P < 0.01. The data represent combined results of three independent experiments. (B) Histopathological examination of the eye on day 25 post-immunization. IL-17–/– mice showed milder infiltration of lymphocytes, macrophages and neutrophils in the retina than WT mice. Re, retina; VC, vitreous cavity. Representative pictures from six mice per group examined. (C) Cytokine production by LN cells. On day 15, LN cells from WT or IL-17–/– mice were collected and CD4+ T cells purified. Cells were cultured with 0, 1.0 and 10 µg ml–1 of IRBP. Supernatants were analyzed for IFN- or IL-17 production by ELISA. (D) Expression of Th1-related genes. Total RNAs were extracted from the eyes of WT and IL-17–/– mice on indicated days post-immunization. Equal amounts of cDNAs, adjusted to β-actin expression levels, were amplified using primers for IFN- and MCP-1. Data shown are representative of three independent experiments.

 
Exacerbation of EAU with over production of IL-17 by blockade of IFN- plus IL-4
While T_h17 differentiation depends on TGF-β in combination with cytokines produced by activated dendritic cells, namely IL-6, IL-1 and tumor necrosis factor- (TNF-) (3, 13), IFN- and IL-4 have been shown to negatively regulate T_h17 differentiation (2, 4). Administration of anti-IL-4 plus anti-IFN- mAb, but not control rat IgG, significantly exacerbated the disease on day 17 and later (Fig. 3A). On day 17, IL-17 production by CD4⁺ T cells from draining LN in response to IRBP stimulation was significantly augmented by the antibody treatment (Fig. 3B). IFN- production in vitro was not affected by the treatment due presumably to substantial T_h1 development in vivo in the presence of IL-12. Of note, anti-IFN- plus anti-IL-4 antibody treatment again affected the later phases of EAU, i.e. on day 17 and later while it did not affect the induction phase of the disease.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3. Exacerbation of EAU by neutralization of anti-IFN- plus anti-IL-4 mAb treatment. (A) WT B6 mice were immunized with IRBP. The immunized mice were treated every other day either with anti-IFN- plus IL-4 mAbs (closed circles; n = 5) or control rat IgG (open circles; n = 5). EAU symptoms in the eye were evaluated from day 7 after immunization. The values represent mean ± SEM. *P < 0.05. (B) On day 17, CD4+ T cells were cultured with 10 µg ml–1 IRBP and supernatants analyzed for IFN- and IL-17 production by ELISA. Data shown are mean ± SEM of triplicate samples and are representative of three independent experiments. *P < 0.01; NS, not significant.

 

	Discussions

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In the present study, we investigated the role of IL-17 and IL-17-producing T_h17 cells in EAU. While IL-17 was produced by CD4⁺ T cells and was detected in the eyes, IL-17 deficiency only affected the late phases of the disease and the severity was not affected at the early phases. Anti-IFN- plus anti-IL-4 antibody treatment and the resultant T_h17 augmentation exacerbated the late phases of the disease but not the induction phases. Given the importance of T_h1 responses especially at the early/induction phases of EAU (5), our data indicated that T_h1 and T_h17 responses are differentially required for EAU.

IL-17, a pro-inflammatory cytokine produced mainly by activated T cells, induces inflammation mainly through release of pro-inflammatory and neutrophil-mobilizing cytokines/chemokines, such as IL-6 and CXCL1 and CXCL8, by target cells (14). Augmented expression of IL-17 is observed in patients with a variety of allergic and autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS) and Behcet's disease, supporting the idea that this inflammatogenic cytokine contributes to the induction, development and/or maintenance of these diseases. Actually, Amadi-Obi et al. (15) reported high expression of IL-17 in human peripheral blood mononuclear cell populations during uveitis. In this report, contribution of T_h17 cells to mouse EAU progression was clearly demonstrated. Additionally, involvement of IL-17 and T_h17 cells was demonstrated in some animal models of diseases, collagen-induced arthritis (16) and EAE (4, 10, 17), experimental models for RA and MS, respectively. Of most importance, Cua et al. (18) clearly demonstrated that the IL-23-T_h17 axis, but not the IL-12-T_h1 axis, is critical for induction of EAE, by taking advantage of IL-23 (p19)-deficient mice with impaired T_h17 development. Curiously, however, Tang et al. (19) recently reported that EAU induced with antigen-pulsed dendritic cells has features distinct from the traditional one induced by immunization of mice with IRBP in complete Freund's adjuvant. This type of EAU is characterized by a mixed T_h1/T_h2 response with minimal IL-17 production. This report along with others suggests that the relative importance of T_h1 and T_h17 cells may differ in distinct forms of experimental (and possibly clinical) uveitis.

In this study, we demonstrated that EAU, an experimental inflammatory disease of autoimmune origin, is induced in IL-17^–/– mice. The induction phase of the disease was not affected by the IL-17 deficiency, while the severity was significantly reduced at later phases in IL-17^–/– mice. Thus, our data demonstrated that IL-17 is not a prerequisite for development of EAU but is involved in the later phases of the disease. Amadi-Obi et al. (15) also demonstrated the involvement of IL-17 and T_h17 cells in EAU induction. In their report, expression of IL-17 in the retina was very low on day 7 after immunization when initial signs of EAU were detectable. Thus, it is reasonable to assume that T_h1 cells rather than T_h17 cells play a role at this stage.

We previously reported that impairment of T_h1 responses by IL-27 receptor (WSX-1) deficiency resulted in suppression of EAU development, especially at early phases (5). In the current study, we demonstrated that IL-17 is not a prerequisite for EAU development. The current and previous studies by our group are seemingly contradictory to previous reports by others that revealed the critical importance of IL-17/T_h17 in EAE (10, 17). In these reports, EAE development was significantly suppressed in IL-23 (p19)-deficient mice concomitant with impairment of T_h17 development, demonstrating that IL-23-induced T_h17 response is crucial for EAE development. In the IL-23-deficient mice, however, T_h1 cells and inflammatory macrophages did enter the central nervous system (CNS) of immunized IL-23^–/– (p19^–/–) mice but failed to induce EAE (18). In addition, cellular infiltration was still observed in the CNS of IL-17^–/– mice, albeit far less than in WT mice (17). It is reasonable to assume that these infiltrating cells play some roles for the induction of EAE, such as induction of sub-clinical local inflammation in the CNS. While degree of paralysis was assessed in EAE scoring, subtle changes such as vascular dilatation, focal or linear lesions vasculitis and soft exudates by ophthalmoscopic examination were assessed in EAU scoring. Higher sensitivity in EAU assessment may be one of the reasons for the apparently distinct requirement for T_h1 and T_h17 cells for the development of EAU and EAE.

EAU has been characterized by T_h1-dominant responses (20) and augmented T_h1 responses resulted in high susceptibility to ocular autoimmunity (21). The current and previous (5) studies by our group also support the importance of T_h1 responses in EAU. Nonetheless, Jones et al. (22) reported the development of EAU in IFN--deficient mice. Although the severity of EAU in IFN--deficient mice was comparable to that in WT mice, cellular infiltrates in the eyes of IFN--deficient mice contained an excess of granulocytes and IL-6-producing cells, which is reminiscent of the effects of IL-17/T_h17 cells. Production of TNF- and IL-6 by LN cells in response to IRBP is also in line with the development of T_h17 cells in the absence of IFN-. Interestingly, while anti-IFN- plus anti-IL-4 antibody treatment augmented T_h17 differentiation in vivo, there was no difference between antibody-treated and untreated mice in the clinical scores by day 14 (Fig. 3A). Given the involvement of IL-17/T_h17 at later phases of EAU as demonstrated in this study, these data along with the development of EAU in IFN--deficient mice may indicate INF--independent mechanism before T_h17 cells participate in the pathogenesis. It is, however, possible that antibodies did not block cytokines produced in the eyes while successfully blocking the effect of IFN- and IL-4 systemically in our experimental system.

In summary, we have demonstrated the differential requirement of two responses—T_h1 at early or induction phases and T_h17 at later or maintenance phases of EAU. Although inflammation induced by each response may be different in property, both responses significantly contribute to the development of EAU during the disease course in a synergistic fashion.

	Funding

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The Ministry of Education, Science, Technology, Sports and Culture of Japan (to H.Y. and A.Y.); Japan Research Foundation for Clinical Pharmacology (to H.Y.); the Naito Foundation (H.Y.); the Takeda Science Foundation (to H.Y.).

	Acknowledgements

 
The authors have no financial conflict of interest.

	Abbreviations

 

CNS, central nervous system

EAE, experimental autoimmune encephalomyelitis

EAU, experimental autoimmune uveoretinitis

IRBP, interphotoreceptor retinoid-binding protein

LN, lymph node

MS, multiple sclerosis

PMA, phorbol myristate acetate

RA, rheumatoid arthritis

TGF-β, transforming growth factor-β

TNF-, tumor necrosis factor-

WT, wild type

	Notes

 
Transmitting editor: T. Watanabe

Received 27 April 2007, accepted 22 November 2007.

	References

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