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CpG-Containing Oligodeoxynucleotide 1826 Converts the Weak Uveitogenic Rat Interphotoreceptor Retinoid-Binding Protein Peptide 1181–1191 into a Strong Uveitogen ¹

Hui Shao^*, Song Lei^*, Sheher L. Sun^*, Jim Xiang, Henry J. Kaplan^* and Deming Sun^2,*

^* Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202; and Departments of Microbiology, Immunology and Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

	Abstract

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Aberrant activation of autoreactive T cells is one of the major causes of autoimmune disease. Autoantigens are sequestered and in many cases weak immunogens. For example, in experimental autoimmune uveitis, immunization of naive rats with autologous interphotoreceptor retinoid-binding protein (IRBP) fails to induce intraocular inflammation or a strong T cell response, whereas bovine IRBP is a strong inducer of experimental autoimmune uveitis. Such observations challenge the view that the autoantigen alone is responsible for the development of autoimmunity. Here, we demonstrate that autologous rat IRBP is converted to a strong immunogen in the presence of a small dose of CpG-containing oligodeoxynucleotides. Our results indicate that specific CpG-containing oligodeoxynucleotides may play an important role in the activation and expansion of autoreactive T cells in vivo, leading to autoimmune disease.

	Introduction

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Uveitis is a common cause of human visual disability and blindness. Its recurrent nature frequently results in severe clinical complications, such as cystoid macular edema, cataract formation, and glaucoma. Uveitis can be associated with various systemic diseases or occur in isolation (1). It is hypothesized that the activation of uveitogenic T cells may result from the cross-reactivity of a self-Ag with microbial Ags or, alternatively, the dysfunction of immune regulation leading to the autoaggressiveness of previously suppressed uveitogenic T cells.

Although autoreactive T cells have been isolated from both healthy humans and naive rodents (2, 3, 4), they are not pathogenic; only those that have been recently activated cause disease (5, 6, 7). Typically, cultured autoreactive T cells can induce a specific autoimmune disease only when freshly reactivated, underscoring the pivotal role of autoreactive T cell activation in the pathogenesis of autoimmunity. The aggressive nature of autoreactive T cells depends on their degree of activation, and studies on T cell activation in vitro have shown that microgram per milliliter concentrations of the relevant Ag are required to activate autoreactive T cells to become pathogenic (7, 8). Such an observation has led to the assumption that if the availability of a given Ag-MHC complex is limited, the pathogenic activation of autoreactive T cells in vivo may require more than one ligand or, alternatively, the activity of already pathogenic autoreactive T cell subsets may be increased through activation by multiple ligands.

Autoimmune disease is closely associated with microbial infection (9, 10, 11, 12), but the relationship between the infection and the initiation of autoimmunity remains unclear. It has been hypothesized that structural mimicry between a microbial Ag and an autoantigen could break tolerance to self-Ags (13, 14, 15, 16). In addition, bacterial and viral toxins can also act as superantigens to activate T cells in a nonspecific fashion (17) or promote T cell activation by enhancing the activity of APCs.

Recent studies have shown that bacterial DNAs play a major role in both innate and adaptive immunity, facilitating the development of autoimmune disease (18, 19, 20). Unmethylated CpG-containing oligodeoxynucleotides (CpG-ODNs) ³ account for the stimulatory effect of bacterial DNA (21, 22, 23, 24). The most active immune stimulatory sequences in mice contain an unmethylated CpG-dinucleotide flanked at the 5'-end by two purines and at the 3'-end by two pyrimidines. Studies in experimental disease models frequently use heat-killed mycobacteria in CFA for the priming of autoreactive T cells in vivo; however, CFA can be completely replaced by bacterial DNA, such as CpG-ODNs (20).

In this study, we show that CpG-ODN₁₈₂₆ had a synergistic effect on the activation of uveitogenic interphotoreceptor retinoid-binding protein (IRBP)-specific T cells by autologous Ag. In vivo-primed lymphoid cells readily transferred disease to naive rats after in vitro exposure to the immunizing Ag in the presence of a small amount of CpG-ODN₁₈₂₆, whereas the same cells exposed to autologous Ag alone were poorly uveitogenic. This observation suggests that CpG-ODN₁₈₂₆ has a potent synergistic effect on the activation of autoreactive T cells in vivo.

	Materials and Methods

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Animals and reagents

Pathogen-free female Lewis rats (5–6 wk old), purchased from Harlan Sprague Dawley (Indianapolis, IN), were housed and maintained at the animal facilities of the University of Louisville. All animal studies conformed to the Association for Research in Vision and Ophthalmology statement on the use of animals in Ophthalmic and Vision Research. Institutional approval was obtained, and institutional guidelines regarding animal experimentation were followed. The bovine and rat IRBP peptides (Fig. 1A) were synthesized by ResGen Invitrogen (Carlsbad, CA). CpG-ODN₁₈₂₆ (5'-TCCATGACGTTCCTGACGTT-3'), and the control ODN₁₉₈₂, a non-CpG-containing ODN (5'-TCCAGGAGTTCTCTCAGGTT-3') (25) were purchased from Qiagen (Alameda, CA); the LPS content of the ODN was <1 ng LPS per mg of DNA, measured using the Limulus amebocyte assay (BioWhittaker, Walkersville, MD).

View larger version (24K): [in this window] [in a new window]   FIGURE 1. rIRBP and bIRBP peptides used for induction of EAU in Lewis rats. A, Sequences of bIRBP1177–1191 (R16) and bIRBP1181–1191 and rIRBP1181–1191; amino acid differences are indicated in bold letters. B, Time course and clinical score of EAU after immunization with each of the three peptides (100 µg/rat). Data are compiled from four separate experiments and are presented as the average score (±SD) for the animals in each group (n = 6).

The induction of uveitis in Lewis rats using IRBP peptides has been previously described (8). Briefly, the rats were immunized s.c. with 200 µl of an emulsion containing 30 µg of bovine IRBP (bIRBP) peptide 1177–1191 (R16) or the corresponding rat peptide and 500 µg of Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI) in IFA (Sigma-Aldrich, St. Louis, MO), distributed over six spots at the tail base and on the flank.

For induction of uveitis by adoptive transfer of R16-specific T cells, naive Lewis rats were injected i.v. with 0.5 ml of PBS containing either in vitro restimulated R16-specific T cells prepared from rats with uveitis induced by Ag immunization or R16-specific T cell lines and then examined daily for clinical signs of uveitis by slit lamp biomicroscopy. The intensity of uveitis was scored blind on an arbitrary scale of 0–4 (8) with: 0 as no disease; 1 as engorged blood vessels in the iris and an abnormal pupil configuration; 2 as a hazy anterior chamber; 3 as a moderately opaque anterior chamber, with the pupil still visible; and 4 as an opaque anterior chamber, obscured pupil, and frequently proptosis. Inflammation of the eye was confirmed by histopathology.

R16-specific T cell lines

R16-specific T cell lines were isolated from R16-immunized Lewis rats as described previously (7, 8, 26, 27, 28). T cells were isolated 10 days postimmunization from lymph node cells or spleen cells by passage through a nylon wool column. The cells (1 x 10⁷) were stimulated with 20 µg/ml R16 in 2 ml of medium in a six-well plate (Costar, Cambridge, MA) in the presence of 2 x 10⁷ irradiated syngeneic spleen cells as APCs. After 2 days, the activated lymphoblasts were isolated by gradient centrifugation in Lymphoprep (Robbins Scientific, Mountain View, CA) and cultured in RPMI 1640 supplemented with 15% IL-2-containing medium (supernatant from Con A-stimulated Lewis rat spleen cells). These T cell lines were maintained by periodic 48-h restimulation (about once every 10 days) with Ag in the presence of irradiated syngeneic APCs and were used after three to four stimulation/resting cycles.

Cell proliferation and cytokine assays

R16-specific T cells (3 x 10⁴ cells/well) or highly enriched T cells from draining lymph nodes, prepared by nylon wool adherence and adsorption by magnetic beads coated with Abs against rat ED1 (macrophage) and CD45R (B cells), in a total volume of 200 µl were cultured at 37°C for 48 h in 96-well microtiter plates with irradiated syngeneic spleen APCs (2 x 10⁵) and medium or IRBP peptide or CpG-ODN₁₈₂₆ alone or in combination; then a fraction of the culture supernatant was analyzed for IL-2 and IFN- production using ELISA kits (R&D Systems, Minneapolis, MN). The plates were then pulsed for 6 h with 0.5 µCi [³H]thymidine per well, and the cells were assessed for isotope incorporation (Packard Instrument, Meriden, CT). The proliferative response was expressed as the mean counts per min ± SD of triplicate determinations.

LDA

Lewis rats were immunized s.c. with 100 µg of IRBP peptide emulsified in CFA and, in some cases, also injected i.p. three times with 60 µg of CpG-ODN₁₈₂₆ on alternate days starting on the day of Ag injection; then the spleen and draining lymph nodes were removed 15 days later, and a single-cell suspension was prepared. T cells were enriched by nylon wool adherence and seeded at 1 x 10⁴ to 3 x 10⁵ cells/well with 24 replicate wells for each cell density in 2 sets of 96-well flat-bottom culture plates containing irradiated spleen cells (1 x 10⁵/well), 1 set of which contained an optimal dose of immunizing peptide (20 µg/ml). After 72 h, the plates were pulsed for 6 h with 0.5 µCi of [³H]thymidine/well, and the cells were assessed for isotope incorporation (Packard Instrument). The number of T cells seeded in each well was based on preliminary LDA estimates of IRBP-reactive cell frequencies.

Pathological examination

For histology, whole eyes were collected, immersed for 1 h in 4% phosphate-buffered glutaraldehyde, then transferred to 10% phosphate-buffered formaldehyde until processed. The fixed and dehydrated tissue was embedded in methacrylate, and 5-µm sections were cut through the pupillary-optic nerve plane and stained with H&E. The presence or absence of disease was evaluated blind by examining six sections cut at different levels for each eye. Severity of EAU was scored on a scale of 0 (no disease) to 4 (maximum disease) in half-point increments, as described previously (8).

Statistical analysis

Data are expressed as the mean ± SD. Each experiment was repeated at least three times. Student’s t test was used to analyze the results.

	Results

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Rat IRBP_1181–1191 is a weak immunogen

We and others have previously shown that Lewis rats immunized with a synthetic peptide representing residues 1177–1191 (R16) of bovine IRBP emulsified in CFA (100 µg/rat) develop uveitis (8, 29). The transfer of R16-specific autoreactive T cell lines to naive rats induces a similar clinical and pathological disease (8). The four N-terminal amino acids of R16 were functionally dispensable, given that the truncated peptide bIRBP_1181–1191 was equally effective in disease induction in vivo (Fig. 1B) and in stimulation of uveitogenic T cells in vitro (data not shown). Comparative studies showed that immunization of naive rats with the same dose of the equivalent rat peptide (rIRBP_1181–1191), which differs from the bovine sequence by only two residues at positions 1188 and 1190 (Fig. 1A), resulted in a very low incidence of disease (Fig. 1B), in agreement with the results of a previous study (29).

Immunization of Lewis rats with a higher dose (200 µg/rat) of rIRBP_1181–1191 induced a very low number of responder T cells as detected by the proliferation assay and LDA (Fig. 2A and Table I). In addition, rIRBP_1181–1191 was a very poor stimulator of bIRBP_1181–1191-specific T cells (Fig. 2B). Finally, after pre-exposure to bIRBP_1181–1191, but not to rIRBP_1181–1191, the R16-specific cell line, IRBP22, induced EAU in recipient rats (data not shown), demonstrating that residues 1188 and 1190 were functionally crucial.

View larger version (16K): [in this window] [in a new window]   FIGURE 2. rIRBP1181–1191 is a poor immunogen and stimulates very low numbers of uveitogenic T cells in vivo and in vitro. A and B, Proliferation assays showing that draining LNCs from rat IRBP1181–1191-immunized rats responded poorly to the immunizing peptide, but strongly to the corresponding bovine peptide (A), and that an established R16-specific uveitogenic T cell line (IRBP22) responded to bIRBP1181–1191 but not to rIRBP1181–1191 (B).

Previous studies have shown that simultaneous exposure of Ag-specific T cells to two distinct T cell ligands can result in synergistic T cell activation (30, 31). We therefore asked whether additional ligands could affect the weak immunogenicity of rIRBP_1181–1191. As shown in Fig. 3A and B, in the presence of 3 µg/ml CpG-ODN₁₈₂₆ the proliferative response of the R16-specific T cell line IRBP22 to rIRBP_1181–1191 was markedly enhanced compared with the ligand alone.

View larger version (22K): [in this window] [in a new window]   FIGURE 3. CpG-ODN1826 greatly enhances the stimulatory effect of rIRBP1181–1191 on uveitogenic T cells in vitro. Activation of the R16-specific T cell line, IRBP22, by rIRBP1181–1191 with () or without () CpG-ODN1826. The results shown are proliferation (A and B) or production of IL-2 (C–E) or IFN- (D--E). CpG-ODN1826 alone () did not induce a significant T cell response (B and E).

Adoptive transfer of EAU by uveitogenic T cells activated by a combination of IRBP and CpG-ODN₁₈₂₆

The activation status of an autoreactive T cell is strongly reflected by its ability to transfer autoimmune disease (27, 28, 32). Fig. 4 shows that IRBP22 cells stimulated by rIRBP_1981–1191 alone were nonuveitogenic, whereas the same number of cells from the same cell line coactivated by rIRBP_1981–1191 and CpG-ODN₁₈₂₆ effectively induced EAU. In addition, cells stimulated by rIRBP_1181–1191 plus CpG-ODN₁₈₂₆ showed a mean proliferative response and cell expansion 10–20 times greater than those stimulated by rIRBP_1181–1191 alone (data not shown), suggesting that the net increase in the uveitogenic potential of T cells activated by IRBP plus CpG-ODN is much greater. Similar results were obtained using three other IRBP-specific T cell lines (data not shown).

View larger version (70K): [in this window] [in a new window]   FIGURE 4. Synergistic stimulatory effect of CpG-ODN1826 and rIRBP1181–1191 on rat uveitogenic T cells in vivo. EAU was induced in recipient Lewis rats by injection of 2 x 106 R16-specific IRBP22 cells after activation by rIRBP1181–1191 with or without CpG-ODN1826. A, Disease course. B and C, Ocular histopathology of adoptively transferred EAU induced by rat IRBP22 T cells activated by rIRBP1181–1191 alone (B) or peptide plus CpG-ODN1826 (3 µg/ml) (C). Eyes were collected 14 days after transfer. The retinal structure in rats injected with 2 x 106 IRBP22 T cells stimulated by rIRBP1181–1191 was almost normal, whereas severe tissue damage was seen in recipients of the same number of T cells activated by IRBP1181–1191 plus CpG-ODN1826. Note the inflammatory infiltrating cells in the vitreous, retina, and choroid and damage to the retinal photoreceptor cell layer. H&E, x200.

To determine possible mechanisms by which CpG-ODN₁₈₂₆ coactivated uveitogenic T cells, highly enriched primed T cells prepared from the draining lymph nodes of rats immunized with R16 were exposed to the immunizing peptide and CpG-ODN₁₈₂₆ either alone or in combination, with or without APCs. In the absence of additional APCs, the primed T cells responded only to the combination of CpG-ODN₁₈₂₆ and R16 (Fig. 5A). The addition of irradiated APCs resulted in a marked response to R16 alone a weak response to CpG-ODN₁₈₂₆ alone and did not result in a significant increase in the T cell response to the peptide/CpG-ODN combination (Fig. 5B).

View larger version (19K): [in this window] [in a new window]   FIGURE 5. T cell stimulation by CpG-ODN1826 is via a synergistic effect with Ag-specific T cell stimulation. Ag-primed T cells were prepared from R16-immunized rats by passage through nylon wool and further depletion of non-T cells by magnetic bead-conjugated Abs against rat ED1 (macrophage) and CD45R (B cells). The T cells (3 x 105/well) were exposed to different doses of the immunizing peptide or CpG-ODN1826 alone or different doses of peptide and 3 µg/ml CpG-ODN1826 in the absence (A) or presence (B) of additional APCs. In A, the plot of R16 is obscured by the plot of CPG-ODN1826, because the data of both plots are close.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

We have previously shown that autologous rat MBP is converted from a weak encephalitogen into a stronger encephalitogen in the presence of a small amount of bacterial superantigen (35). In the present study, we showed that autologous rat IRBP became a potent uveitogen in the presence of small amounts of CpG-ODN₁₈₂₆, leading to increased activation of uveitogenic T cells. Thus, our observations suggest that the autoantigen alone may not be sufficient to activate autoreactive T cells in vivo and that a T cell ligand(s) other than the autoantigen may be needed to activate uveitogenic T cells in vivo.

Two different T cell ligands can cause synergistic activation of T cells (30). Recently, it has become apparent that CpG-ODNs are strong inducers of innate immunity and promote the generation of adaptive immunity, functioning as potent vaccine adjuvants in mice and primates (22, 36, 37, 38, 39, 40, 41). These molecules have been shown to activate dendritic cells, macrophages, and NK cells (42); induce B cells to proliferate and to secrete Ig (43); and switch an established Th2 response to a Th1 response (44). In our study, we found that rIRBP_1181–1191 was much weaker at stimulating uveitogenic T cell activation and cytokine production than the equivalent bovine peptide, even at a 10-fold higher concentration; similarly, CpG-ODN₁₈₂₆ alone was not a strong stimulator for uveitogenic T cells. However, a robust T cell response was initiated when both molecules were present. This suggests that neither autoantigen nor bacterial DNA alone is sufficient to cause autoimmune uveitis but that the synchronized effect of the two molecules readily results in disease.

We have recently shown ⁴ that adoptively transferred EAU induced by the transfer of R16-specific T cell subsets causes a relapsing uveitis, in contrast to the uveitis induced by active immunization with R16 which is acute and monophasic. The severity of disease and the frequency of relapses depended on the number and activation status of the uveitogenic T cells transferred. In studies reported here, we found that in vitro stimulation of R16-specific T cells with both R16 and CpG-ODN₁₈₂₆ before transfer to naive rats resulted in more severe uveitis, earlier disease onset, and more relapses than stimulation with R16 alone. Thus, CpG-ODN₁₈₂₆ appears to play an important role in the activation and expansion of autoreactive T cells both in vitro and in vivo, thereby altering the pathogenesis of this autoimmune disease.

The optimal effective dose for a given CpG-ODN appears to be narrow. We have observed that the most effective dose of CpG-ODN₁₈₂₆ for primed lymphoid T cells is 1–3 µg/ml, whereas that for established autoreactive T cell lines appears to be wider (data not shown). Interestingly, the stimulatory dose of ODN₁₉₈₂ is 10 times higher than that of ODN₁₈₂₆ (data not shown), suggesting that ODNs should not be classified as effective or ineffective but that each ODN sequence may have its optimal effective concentration.

The mechanisms by which CpG-ODNs enhance T cell activation in vivo and in vitro remain unclear. The impressive adjuvant effects of bacterial DNA and CpG-ODNs may be due to their capacity to activate APCs. Our results (Fig. 5) show that CpG-ODN₁₈₂₆ was a strong costimulator of in vivo-primed R16-specific T cells but itself weakly provoked an in vitro response of primed T cells. It therefore appears that CpG-ODN₁₈₂₆ only increased the response of Ag-primed T cells in the presence of the antigenic peptide. CpG-ODN₁₈₂₆ also decreased the threshold for T cell activation, because a response to the peptide/CpG-ODN combination was with or without professional APCs. However, the possibility that there is a small but significant numbers of APCs present in this T cell-enriched population cannot be excluded. The fact that in the presence of CpG-ODN autoreactive T cells are activated by a lower concentration of autoantigen and by fewer APCs (Fig. 5) appears to agree with the previous observations that bacterial and viral infections exacerbate autoimmune disease by decreasing the threshold of T cell activation, leading to increased activation of autoreactive T cells. The other mechanisms that CPG-ODN increases the development of autoimmunity may include enhancing NKT-T cell interaction and epitope spreading. These mechanistic studies are currently undergoing in our laboratories.

In summary, the results presented in this report show that CpG-ODNs derived from bacterial DNA have a strong potential to induce activation of uveitogenic T cells and supports our hypothesis that autoimmune uveitis may involve costimulation of uveitogenic T cells by autoantigen (e.g., IRBP) and additional T cell ligands, such as bacterial DNA. These observations may provide new insight into the pathogenesis of autoimmune diseases in general.

	Acknowledgments

 
We thank Dr. Thomas Barkas for his assistance in manuscript preparation.

	Footnotes

 
¹ This work was supported in part by Grants NEI EY12974 (to H.S.) and NEI EY014-366 (to D.S.), and Research to Prevent Blindness, Inc., New York City, NY, and Kentucky. H.S. is a recipient of a career development award from Research to Prevent Blindness. H.J.K. is supported by the Commonwealth of Kentucky Research Challenge Trust Fund.

² Address correspondence and reprint requests to Dr. Deming Sun, Department of Ophthalmology and Vision Sciences, Kentucky Lions Eye Center, University of Louisville, 301 East Muhammad Ali Boulevard, Louisville, KY 40202. E-mail address: d0sun001{at}louisville.edu

³ Abbreviations used in this paper: CpG-ODN, CpG-containing oligodeoxynucleotides; EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-binding protein; rIRBP, rat IRBP; bIRBP, bovine IRBP; R16, bIRBP peptide 1177–1191; LDA, limiting dilution analysis; MBP, myelin basic protein.

⁴ H. Shao, S. Lei, S. L. Sun, H. J. Kaplan, and D. Sun. Conversion of monophasic to recurrent autoimmune disease by autoreactive T cell subsets. Submitted for publication.

Received for publication June 18, 2003. Accepted for publication August 14, 2003.

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