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Cutting Edge: Role of Macrophage Migration Inhibitory Factor in Inhibiting NK Cell Activity and Preserving Immune Privilege¹

R. S. Apte^*, D. Sinha, E. Mayhew^*, G. J. Wistow and J. Y. Niederkorn^2,*

^* Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and Section on Molecular Structure and Function, National Eye Institute, National Institutes of Health, Bethesda, MD 20892

	Abstract

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The absence of MHC class I Ags on the corneal endothelium, which lines the anterior chamber of the eye, makes this cell layer potentially vulnerable to lysis by NK cells. However, aqueous humor (AH), which bathes the corneal endothelium, contains a 12-kDa protein which inhibits the NK-mediated lysis of corneal endothelial cells. An amino acid sequence analysis of AH revealed that this factor shared >90% homology with macrophage migration inhibitory factor (MIF). The NK inhibitory effect of AH was neutralized with anti-human MIF Ab. Moreover, mouse rMIF produced a similar inhibition of NK cell activity. However, neither rMIF nor AH inhibited the CTL-mediated lysis of allogeneic cells. rMIF prevented the release of perforin granules by NK cells but not CTLs. Although MIF displays proinflammatory properties, these results indicate that it can also inhibit at least one immune effector element, NK cells, and thereby contribute to immune privilege in the eye.

	Introduction

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The anterior chamber (AC)³ of the eye is a classic example of an immunologically privileged site in which tumor and tissue allografts escape immunologic rejection (1, 2). It is becoming increasingly clear that multiple mechanisms sustain immune privilege in the eye and the brain (1). Ags introduced into the AC elicit a unique Ag-specific down-regulation of systemic delayed-type hypersensitivity that reduces the risk of immune-mediated injury to delicate ocular tissues having little or no capacity for regeneration (1, 2). The expression of immune-mediated inflammation is also suppressed by a myriad of immunosuppressive factors present in the aqueous humor (AH) (1). The widespread expression of Fas ligand within the eye also contributes to immune privilege by inducing apoptosis of inflammatory cells that enter the eye (2).

The corneal endothelial cells that line the AC are terminally differentiated cells that possess minimal regenerative potential. These cells function as osmotic pumps to maintain corneal hydration and clarity; injury to the corneal endothelium, either immune-mediated or otherwise, leads to blindness (3). Similarly, the posterior surface of the AC is formed by the epithelium of the lens, whose clarity is also essential for vision.

Both corneal endothelial cells and lens epithelial cells express little or no MHC class I Ags; as a result, these two cell types are highly vulnerable to lysis by NK cells (4, 5, 6). NK cells are known to traffic into the eye under many conditions, yet NK-mediated injury to the corneal endothelium is rare (7). This appears to be due to the presence of a 12-kDa protein present in the AH that produces an immediate and profound inhibition of NK cell-mediated cytolysis (4). In the present study, we isolated this factor, subjected it to amino acid (aa) sequence analysis, and determined that it had >90% sequence homology with the proinflammatory cytokine, macrophage migration inhibitory factor (MIF). The results also demonstrate that MIF inhibits NK cell-mediated cytotoxicity by preventing the release of cytolytic perforin granules.

	Materials and Methods

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Aqueous humor

AH was obtained from rabbit and mouse eyes by paracentesis as described previously (4).

Mouse rMIF

MIF belongs to a superfamily of small isomerases that are found in a wide variety of tissues, including the lens, cornea, brain, and pituitary gland (8, 9, 10, 11). RT-PCR of mouse lens RNA was used to amplify the coding sequence for mouse MIF using primers 5'-TCCGCCCATATGCCTATGTTCATCGTGAACACC and 3'-AGCGGTGGATCCAAGTGGGGCCAGGACTCAAGC, which incorporated the NdeI (5') and BamHI (3') restriction sites. The cDNA was initially cloned into the pCRII vector (Invitrogen, San Diego, CA), sequenced, and then subcloned into the NdeI and BamHI sites of the pET-17b vector (Novagen, Madison, WI). Following the manufacturer’s protocols, protein was expressed in pLysS cells and induced with 0.4 mM isopropyl ß-D-thiogalactoside for 3 h at 25°C. MIF protein was isolated by ion-exchange chromatography on High Performance Q-Sepharose (Pharmacia Biotech, Piscataway, NJ) and by gel filtration using a Superdex 75pg column (Pharmacia).

NK cell culture and cytotoxicity assays

Lymphokine-activated killer cells, which are highly enriched for NK cells, were prepared from C57BL/6 (H-2^b) and C3H/HeJ (H-2^k) mice as described elsewhere and used in a conventional 4-h ⁵¹Cr release assay (12). Neutralization of the NK inhibitory effect of AH was performed by incubating rabbit AH with polyclonal anti-human MIF IgG Ab (600 µg/ml; R&D Systems, Minneapolis, MN) for 1 h at 4°C. Controls consisted of rabbit AH treated in the same manner with normal goat IgG (600 µg/ml; Organon Teknika, West Chester, PA).

Corneal endothelial cell cultures and cytotoxicity assay

Mouse corneal endothelial cells are terminally differentiated and cannot undergo mitosis. Therefore, long term mouse corneal endothelial cell lines were established from C3H (H-2^k) mice by transducing freshly isolated cells with the human papilloma virus genes E6 and E7 (13). These cells proliferate indefinitely while maintaining their original morphologic characteristics (13).

MIF assays

MIF activity was analyzed in a conventional capillary tube assay (14). The average area of macrophage migration (mm²) was calculated for each group by image analysis. Data are represented as the percentage of inhibition of macrophage migration after 24 h as compared with control medium. The percentage of inhibition of migration was calculated using the following formula: ([control migration - experimental migration] ÷ control migration) x 100.

MIF in rabbit and mouse AH was quantified using a direct competition ELISA as described previously (15). Mouse rMIF was used as the standard, and goat anti-human MIF Ab (IgG; R&D Systems) was used as the primary Ab. Rabbit anti-goat IgG conjugated with horseradish peroxidase (Accurate Chemical and Scientific, Westbury, NY) served as the secondary Ab.

Granule exocytosis assay

The release of sodium benzyloxycarbonyl-L-lysine-thiobenzylester-esterase from NK cells was determined using a modified method of Green and Shaw (16). One group of cells was frozen and thawed twice to obtain maximum granule release. Granule release was calculated according to the following formula: percentage of granule release = (experimental reading - background reading) ÷ (maximum reading - background reading) x 100.

Generation of allospecific CTLs

Allospecific CTLs were generated in vitro by incubating C57BL/6 (H-2^b) spleen cells with -irradiated (3000 cGy) P815 mastocytoma (DBA/2; H-2^d) stimulator cells for 5 days at 37°C. In vitro-primed C57BL/6 spleen cells were washed and used as effector cells in a 4-h ⁵¹Cr release assay using radiolabeled P815 target cells as described previously (4). Cytotoxicity assays were performed in the presence of either MIF (10 µg/ml) or DMEM alone. Naive controls consisted of freshly isolated, unstimulated C57BL/6 spleen cells. The E:T ratio was 100:1.

	Results

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Partial aa sequence of NK cell-inhibitory factor

Rabbit AH was subjected to SDS-PAGE, transferred to a polyvinylidene difluoride membrane, stained with Coomassie blue, and subjected to tryptic digestion before HPLC microsequencing. The 14-aa internal sequence obtained was subjected to a BLAST network database search (National Center of Biotechnology Information, Bethesda, MD). Table I shows the strong sequence homology between the rabbit AH sequence and MIF (aa 95–108) sequences from various other species. This homology permitted us to confirm the presence of MIF in the AH from various species using anti-human MIF Ab. In multiple ELISAs, MIF was detected in mouse, rat, rabbit, cow, horse, and human AH (data not shown). Rabbit and mouse AH contained 8.6 ± 1.84 µg/dl and 5.4 ± 1.41 µg/dl of MIF, respectively. Moreover, we have also confirmed the presence of MIF in mouse and rat AH by Western blot analysis (data not shown). These findings are in agreement with the recent results of Matsuda et al. who detected MIF in cells lining the AC and in the AH of rats (9, 17).

MIF was originally defined by the capacity of supernatants from activated lymphocytes to prevent the random migration of macrophages (18). Additional experiments were performed to confirm that the 12-kDa protein in AH possessed functional MIF activity using a conventional macrophage migration inhibition assay (14). The results shown in Figure 1 demonstrate that AH and functional rMIF significantly inhibited macrophage migration as compared with control medium. The MIF activity of AH was comparable with that shown by 10 µg/ml of wild-type murine rMIF.

View larger version (27K): [in this window] [in a new window]   FIGURE 1. Effect of rabbit AH and murine rMIF on random macrophage migration. A, Capillary tubes were filled with C57BL/6 spleen cells and incubated with complete RPMI 1640 only or complete RPMI 1640 containing either 50% AH or 10 µg/ml of murine rMIF. The data are reported as the percentage of inhibition of macrophage migration after 24 h as compared with control medium. n = 3 to 4 for each group. * p = 0.0001 for 50% AH, and p = 0.017 for MIF, compared with the RPMI 1640 control. B, Representative samples of macrophage migration in complete RPMI 1640 (top) and RPMI 1640 containing 50% AH (bottom).

If the NK inhibitory effect of AH was attributable to MIF, it should be possible to produce a similar inhibition of NK cell activity with murine rMIF. This possibility was tested using YAC-1 lymphoma target cells and lymphokine-activated killer cells as an enriched source of NK cells. rMIF showed a significant dose-dependent inhibition of the NK cell-mediated cytolysis of YAC-1 cells (Fig. 2A). To test the physiologic relevance of these findings in the context of immune privilege, MIF was assayed for its ability to inhibit the NK cell-mediated lysis of syngeneic C3H corneal endothelial cells. The results show that rMIF produced a profound dose-dependent inhibition of the NK cell-mediated lysis of syngeneic corneal endothelial cells (Fig. 2B). An inhibition of NK cell-mediated lysis was also observed with other NK-sensitive target cells, including RMA-S lymphoma cells, BALB/c Con A blasts, and TAP -/- Con A blasts (data not shown). However, the inhibitory effects of MIF and AH were specific for NK cell-mediated cytotoxicity, since the CTL-mediated lysis of allogeneic target cells was unaffected by MIF (Fig. 3).

View larger version (15K): [in this window] [in a new window]   FIGURE 2. Effect of mouse rMIF on NK cell-mediated lysis. In vitro assays were performed in the presence of murine rMIF at the concentrations indicated in parentheses. The results are expressed as the mean ± SEM. A indicates assays using YAC-1 lymphoma target cells. B indicates assays using syngeneic C3H/HeJ corneal endothelial target cells. These experiments were performed three times with similar results.

View larger version (13K): [in this window] [in a new window]   FIGURE 3. Mouse rMIF does not affect allospecific CTL activity. C57BL/6 (H-2b) anti-DBA/2 (H-2d) allospecific CTLs were generated in vitro. In vitro-primed C57BL/6 spleen cells were used as effector cells in a 4-h 51Cr release assay using radiolabeled P815 target cells. Assays were performed in the presence of either functional mouse rMIF (10 µg/ml) or DMEM alone. The naive control consisted of freshly isolated, unstimulated C57BL/6 spleen cells. The E:T ratio was 100:1. The results are expressed as the mean cytotoxicity ± SEM. This experiment was performed twice with similar results.

To confirm that the inhibitory activity of AH was solely attributable to MIF, AH was treated with anti-MIF antiserum before use in NK cytolysis assays. Treatment with polyclonal goat anti-human MIF Ab almost completely eliminated the AH-mediated inhibition of NK cell cytotoxicity, while an isotype-matched control Ab had no effect on the AH-mediated inhibition of NK cytolysis (Fig. 4).

View larger version (11K): [in this window] [in a new window]   FIGURE 4. Neutralization of the NK inhibitory effect of AH with anti-MIF Ab. Rabbit AH was pretreated with either goat anti-human MIF IgG Ab (600 µg/ml) or normal goat IgG before use in the in vitro NK cytolysis assay with YAC-1 lymphoma target cells. The results are expressed as the mean cytolysis ± SEM. Differences between anti-MIF-treated AH and normal goat IgG-treated AH were significant (p = 0.02). This experiment was performed three times with similar results.

The capacity of MIF to produce an immediate and profound inhibition of NK cell-mediated cytolysis suggests that MIF either kills NK cells or blocks their cytolytic function (i.e., the release of cytolytic perforin granules). However, incubating NK cells in MIF (10 µg/ml) for 4 h did not adversely affect NK cell viability (MIF-treated NK cells = 94% viable; control medium = 97% viable). Moreover, an assessment of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining indicated that a 4-h incubation in 50% AH did not induce NK cell apoptosis (<1% NK cell apoptosis in both AH-treated and control medium groups). By contrast, exposure to MIF resulted in a marked inhibition of perforin granule exocytosis by NK cells but not by CTLs (Fig. 5).

View larger version (16K): [in this window] [in a new window]   FIGURE 5. MIF-mediated inhibition of NK cell granule exocytosis. NK cells were incubated in medium or rMIF (10 µg/ml) and assessed for the exocytosis of perforin granules. Perforin granule release was also determined for C57BL/6 allospecific CTLs incubated in medium alone or medium containing rMIF (10 µg/ml). Untreated NK cells and allospecific CTLs were subjected to two freeze-thaw cycles to obtain maximum granule release values (values equaling 100% granule exocytosis).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

A growing body of evidence indicates that ocular immune privilege is a composite of multiple mechanisms that selectively down-regulate those immune effector mechanisms which have the capacity to inflict irreparable damage upon nonregenerative ocular tissues. The present findings suggest that MIF is yet another participant in this process. It is noteworthy that MIF is produced and stored in both the brain and the eye, two classic immune-privileged sites that do not express MHC class I Ags and consequently are vulnerable to NK cell-mediated cytolysis. In the eye, MIF is one of several cytokines with immunosuppressive characteristics. However, unlike other AH-borne cytokines, such as TGF-ß, the suppressive effects of MIF are restricted to NK cells. The immediate suppression of NK cell-mediated lysis produced by MIF is crucial, because even minimal damage to the nonregenerative corneal endothelium can lead to blindness. The lens also fails to express MHC class I determinants; as such, it is theoretically vulnerable to NK cell-mediated injury. Immune damage to the lens would lead to cataract formation. However, the lens forms the posterior boundary of the AC and is bathed in AH. As a result, the lens is protected from NK cell-mediated damage.

The present study adds to a growing body of evidence indicating that MIF is ubiquitous and pleiotropic. The ability of MIF to produce an immediate and profound inhibition of NK cell-mediated lysis demonstrates for the first time that MIF can also function as an immunosuppressive cytokine.

	Footnotes

 
¹ This work supported by National Institutes of Health Grants EY05631 and EY 7641 and by an unrestricted grant from Research to Prevent Blindness, New York, NY.

² Address correspondence and reprint requests to Dr. Jerry Y. Niederkorn, Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9057. E-mail address:

³ Abbreviations used in this paper: AC, anterior chamber; AH, aqueous humor; MIF, macrophage migration inhibitory factor; aa, amino acid.

Received for publication January 20, 1998. Accepted for publication April 14, 1998.

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				R. Abe, T. Peng, J. Sailors, R. Bucala, and C. N. Metz Regulation of the CTL Response by Macrophage Migration Inhibitory Factor J. Immunol., January 15, 2001; 166(2): 747 - 753. [Abstract] [Full Text] [PDF]

				K. Ohta, S. Yamagami, A. W. Taylor, and J. W. Streilein IL-6 Antagonizes TGF-{beta} and Abolishes Immune Privilege in Eyes with Endotoxin-Induced Uveitis Invest. Ophthalmol. Vis. Sci., August 1, 2000; 41(9): 2591 - 2599. [Abstract] [Full Text]

				A. C. Repp, E. S. Mayhew, S. Apte, and J. Y. Niederkorn Human Uveal Melanoma Cells Produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells J. Immunol., July 15, 2000; 165(2): 710 - 715. [Abstract] [Full Text] [PDF]

				K. Ohta, B. Wiggert, S. Yamagami, A. W. Taylor, and J. W. Streilein Analysis of Immunomodulatory Activities of Aqueous Humor from Eyes of Mice with Experimental Autoimmune Uveitis J. Immunol., February 1, 2000; 164(3): 1185 - 1192. [Abstract] [Full Text] [PDF]

				M. Tanigawa, J. E. Bigger, M. Y. Kanter, and S. S. Atherton Natural Killer Cells Prevent Direct Anterior-to-Posterior Spread of Herpes Simplex Virus Type 1 in the Eye Invest. Ophthalmol. Vis. Sci., January 1, 2000; 41(1): 132 - 137. [Abstract] [Full Text]

				F. Arcuri, M. Cintorino, R. Vatti, A. Carducci, S. Liberatori, and L. Paulesu Expression of Macrophage Migration Inhibitory Factor Transcript and Protein by First-Trimester Human Trophoblasts Biol Reprod, June 1, 1999; 60(6): 1299 - 1303. [Abstract] [Full Text]

				J. Matsunaga, D. Sinha, L. Pannell, C. Santis, F. Solano, G. J. Wistow, and V. J. Hearing Enzyme Activity of Macrophage Migration Inhibitory Factor toward Oxidized Catecholamines J. Biol. Chem., February 5, 1999; 274(6): 3268 - 3271. [Abstract] [Full Text] [PDF]

D. V. Pastrana, N. Raghavan, P. FitzGerald, S. W. Eisinger, C. Metz, R. Bucala, R. P. Schleimer, C. Bickel, and A. L. Scott Filarial Nematode Parasites Secrete a Homologue of the Human Cytokine Macrophage Migration Inhibitory Factor Infect. Immun.,