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(Journal of Leukocyte Biology. 2001;70:277-282.)
© 2001 by Society for Leukocyte Biology

MC148 encoded by human molluscum contagiosum poxvirus is an antagonist for human but not murine CCR8

Hans R. Lüttichau*,{dagger}, Jan Gerstoft{dagger} and Thue W. Schwartz*,{ddagger}

* Laboratory for Molecular Pharmacology, Department of Pharmacology, Panum Institute,
{dagger} Department for Infectious Diseases, Rigshospitalet, and
{ddagger} 7TM Pharma A/S, Copenhagen, Denmark.

Correspondence: Hans Rudolf Lüttichau, Laboratory for Molecular Pharmacology, Panum Institute 18/6, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. E-mail: hrl{at}molpharm.dk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The viral CC chemokines MC148, encoded by the poxvirus molluscum contagiosum, and viral macrophage inflammatory protein (vMIP)-I and vMIP-II, encoded by human herpesvirus 8, were probed on the murine CC receptor (CCR) 8 in parallel with human CCR8. In calcium mobilization assays, vMIP-I acted as a high-affinity agonist, whereas vMIP-II acted as a low-affinity antagonist on the murine CCR8 as well as the human CCR8. MC148 was found to bind and block responses through the human CCR8 with high affinity, but surprisingly MC148 was unable to bind and block responses through the murine CCR8. Because MC148 is the only high-affinity antagonist known to target and be selective for CCR8, MC148 is a valuable tool to decipher the role played by CCR8 in the immune system. This study shows that MC148 could not be used in murine inflammatory models; however, it will be interesting to see whether it can be used in other animal models to delineate the role played by CCR8.

Key Words: vMIP-I • vMIP-II • HHV8 • MCV


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the last decade herpesviruses and poxviruses have been found to encode proteins that target the humane chemokine system. These virally encoded proteins can be divided into three groups—chemokines, chemokine receptors, and chemokine-binding proteins. Besides illustrating interaction between virus and host, some of these proteins provide the tools to understand the role played by host-encoded chemokines and chemokine receptors.

Chemokines are 70- to 80-amino-acid proteins with well-characterized three-dimensional structures usually stabilized by two disulfide bridges. They are involved in attracting and activating distinct leukocyte subsets [1 2 3 ]. The precise number of human chemokines has not been determined but is likely to be around 50. They are divided into four families on the basis of the pattern of the conserved cysteine residues located near their N termini and forming disulfide bridges with cysteines located further toward the C termini in the molecules. In the CC family, the two N-terminal cysteines are adjacent; in the CXC family the two residues are separated by a single amino acid; and in the CX3C family the separation is by three amino acids. The XC family, which as yet has one member, has only one cysteine near the N terminus. Chemokines exert their function through seven-transmembrane (7TM), G-protein-coupled receptors of which 11 are CC chemokine receptors (CCRs), 6 are CXC chemokine receptors (CXCRs), 1 is a CX3C chemokine receptor, and 1 is an XC chemokine receptor [3 ].

The lymphocytropic herpesviruses such as human herpesvirus (HHV) 6, HHV7, HHV8, and cytomegalovirus (CMV) have all been found to encode 7TM chemokine receptors [4 5 6 7 8 9 ]. Epstein-Barr virus does not encode a 7TM receptor; instead it has been found to up-regulate the encoding of human CCR (hCCR) 7 and EBI-II receptors [10 ]. A function has not been identified for most of these receptors except for the HHV8-encoded open reading frame 74, which may function as an oncogene due to its high constitutive activity [9 11 12 13 ] and the CMV-encoded US28, which might function as a chemokine scavenger [14 ] and might as well be involved in cellular transfer of the virus [15 ].

Most animal and human poxviruses have been found to encode a protein, vCCI, with the ability to bind members from the CC chemokine family [16 17 18 ]. Furthermore, the murine {gamma}-herpesvirus 68 has been found to encode another protein, M3, which binds several CC chemokines [19 ]. The function of these proteins could very well be to block the inflammatory response from the host.

Finally, the large DNA viruses encode several chemokines. A number of these chemokines have been shown to act as agonists; others have been shown to act as antagonists, and others are still uncharacterized. The CMV-encoded chemokine vCXC1 has been shown to act as a CXCR2 agonist, and this function was suggested to aid in viral dissemination [20 ]. The HHV8-encoded chemokine vMIP-I has been found to act as a CCR8 agonist [21 22 ], and vMIP-III has been found to act as a CCR4 agonist [23 ]. These chemokines may help the virus to evade an antiviral T-helper (Th) 1 immune response by directing the response in a Th2 direction, because CCR4 and CCR8 are encoded on Th2 cells. We have shown that the HHV8-encoded vMIP-II functions as a broad-spectrum chemokine antagonist by blocking six receptors from all four chemokine receptor subfamilies [24 25 ]. Presumably the function of vMIP-II is to block the recruitment of leukocyte subsets necessary for an antiviral response. In contrast, we found MC148, the chemokine encoded by the skin-tropic molluscum contagiosum poxvirus (MCV), to be a highly selective CCR8 antagonist when it was tested on a panel of 16 categorized humane chemokine receptors [25 ]. The CXC chemokine vCXC2 encoded by CMV [26 ] and the CC chemokine U83 encoded by HHV6 [27 ] have so far not been characterized on individual cloned chemokine receptors.

The characterization of these virally encoded chemokine elements has provided tools to decipher the role of the chemokine elements encoded by the host. Thus, vCCI can, when used in animal models, show the role played by CC chemokines in the inflammatory response [16 , 28 , 29 ]. Furthermore, vMIP-II has been shown to reduce the inflammatory response in a rat model of glomerulonephritis [30 ].

MC148 is the only known high-affinity CCR8 antagonist. Therefore, this viral protein is a valuable tool in evaluating the role of the CCR8 receptor. However, when using animal models it is obviously important to characterize these proteins on specific animal chemokine receptors. Here we report the characterization of the virally encoded proteins vMIP-I, vMIP-II, and MC148 (Fig. 1 ) on the murine CCR (mCCR) 8 receptor, done in parallel with the hCCR8.



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  		Figure 1. Alignment of known ligands for the mCCR8 and the hCCR8 receptors. vMIP-I, vMIP-II, MC148, I-309, and TCA-3 were aligned using ClustalW 1.8 software. Identical amino acids are shown in white on black, whereas similar amino acids are shown in white on gray. Asterisks indicate Cys residues.

 

   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Chemokines
The endogenous human ligand I-309 and vMIP-I were from R&D (Minneapolis, MN), T-cell activation protein (TCA)-3 was from PharMingen (San Diego, CA), and vMIP-II was kindly provided by T. Wells (Serono, Geneva, Switzerland). Recombinant MC148 was produced as described previously [25 ]; briefly, cell media from cultures of COS7 cells transfected with the MC148 gene were collected and purified on a cation exchange column followed by reverse-phase high-pressure liquid chromatography. The elution position of the recombinant MC148 protein as well as the purity was identified by mass spectroscopy and NH2-terminal sequence analysis on an ABI 494 protein sequencer (Applied Biosystems, Foster City, CA).

Cloning of mCCR8
A 5.5-kb SacI fragment containing the genomic mCCR8 was provided by Sergio Lira (Schering-Plough, Kenilworth, NJ). The mCCR8 gene was amplified by PCR and inserted into the pTEJ8 vector. Start and end primers were designed from a GenBank sequence (accession no. NM007720). Nucleotide sequence analysis was performed on an ABI 310 sequence system (Perkin-Elmer). The sequence of mCCR8 was identical to that of the GenBank sequence.

Stable cell lines
mCCR8 was transfected into Chinese hamster ovary (CHO) cells using the GenePorter transfection reagent (Gene Therapy Systems, San Diego, CA) according to the supplier’s instructions to establish pool clones, which subsequently were tested in calcium mobilization assays with TCA-3. mCCR8 and hCCR8 were transfected into the murine pre-B-cell line L1.2 by electroporation, and stable transfectants were obtained after limiting dilution and chemical selection with the selection agent geneticin ("G418") and subsequent functional selection by testing the clones for calcium response to TCA-3 and I-309, respectively. In addition an L1.2 cell line expressing hCCR8 established at ICOS (Seattle, WA) was also used.

Binding
Whole-cell binding (2.0 x105 cells per well) was performed at 4°C for 3 h in 0.5 mL of 25 mM HEPES buffer containing 1 mM CaCl2 and 5 mM MgCl2 at pH 7.2, supplemented with 0.5% bovine serum albumin on transiently transfected COS-7 cells. The incubation was stopped by washing four times with 0.5 mL of ice-cold binding buffer made 0.5 mM in NaCl. Cell-associated radioactivity was determined after extraction of the cells with 8 M urea in 3 M acetic acid supplemented with 1% Nonidet P-40. Nonspecific binding, determined in the presence of the relevant chemokine peptide (0.1 µM), was subtracted. 125I-labeled MC148 was prepared in house by Bolton-Hunter iodination prior to high-pressure liquid chromatography purification.

Calcium mobilization experiments
L1.2 cells stably transfected with mCCR8 and hCCR8 and CHO cells stably transfected with mCCR8 were loaded with Fura-2AM (Molecular Probes, Eugene, OR) in RPMI 1640 with 1% fetal calf serum for 20–30 min and washed in the same buffer. Aliquots comprised 106 cells. Each aliquot was pelleted and resuspended in 500 µL of phosphate-buffered saline plus 1% fetal calf serum with 10 mM EGTA. Fluorescence was measured on a Jobin Yvon FlouroMax-2 (Jobin Yvon Spex, Edison, NJ) as the ratio of emission at 490 nm when excited at 340 nm and 380 nm.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Previously, we have shown that MC148 binds hCCR8 with subnanomolar affinity. To see whether MC148 could bind mCCR8, we transfected this receptor and the hCCR8 into COS-7 cells and tested them against MC148 in homologue-binding assays. It was surprising that 125I-labeled MC148 was unable to bind mCCR8, whereas the viral protein bound hCCR8 with high affinity (50% inhibitory concentration, 0.27 nM; 95% confidence interval; 0.20–0.37 nM) (Fig. 2 ). To see whether this effect could be caused by low surface expression of the receptor, we stably transfected CHO cells with mCCR8 and tested the cells against TCA-3 in calcium mobilization experiments. The cells exhibited calcium responses to TCA-3, proving that the receptor was indeed expressed at the cell surface. However, 125I-labeled MC148 was unable to bind to the mCCR8-transfected CHO cells [data not shown], indicating that either MC148 is not a ligand for mCCR8 or the Bolton-Hunter group of 125I-labeled MC148 interferes with the binding to mCCR8.



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  		Figure 2. Homologous competition binding experiments with recombinant MC148 for hCCR8 and mCCR8. Homologous MC148 binding curves are shown for hCCR8 ({circ}) and mCCR8 (•). n = 3.

 
Stable L1.2 cell lines expressing mCCR8 and hCCR8 were generated to test the virally encoded ligands vMIP-I, vMIP-II, and MC148, all of which have been found to target the hCCR8, against the mCCR8.

In calcium mobilization assays, the mCCR8-expressing L1.2 cell line was found to respond to the endogenous murine ligand TCA-3, as well as I-309 and vMIP-I, with potencies for all three chemokines in the subnanomolar range (Fig. 3 ). In contrast, the hCCR8-expressing cell line was found to respond to the endogenous human ligand I-309 as well as vMIP-I with potencies in the subnanomolar range, but this cell line barely showed a response to submicromolar concentrations of TCA-3 (Fig. 3) .



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  		Figure 3. Dose-response curves of calcium mobilization by the agonists I-309, TCA-3, and vMIP-I for L1.2 cells stably transfected with hCCR8 and mCCR8. I-309, TCA-3, or vMIP-I at concentrations of 10-7, 10-8, 10-9, and 10-10 M or vehicle was added to the cells at 50 s. One representative assay out of two is shown for each agonist.

 
Cross-desensitization experiments were done using the three agonists on the hCCR8 as well as the mCCR8 receptors. On the hCCR8 receptor, the viral chemokine vMIP-I was unable to cross-desensitize the response to the endogenous human ligand I-309, whereas I-309 could cross-desensitize the response to vMIP-I (Fig. 4 ). On the mCCR8, vMIP-I and I-309 were unable to cross-desensitize the response to the endogenous murine ligand TCA-3, whereas TCA-3 could cross-desensitize the response to both vMIP-I and I-309. Furthermore, vMIP-I and I-309 were able to cross-desensitize the response to each other. These data suggest that I-309 interacts with at least one site or conformational form of hCCR8 not bound by vMIP-I. Likewise, TCA-3 interacts with at least one conformational form of mCCR8 bound neither by I-309 nor vMIP-I.



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  		Figure 4. Cross-desensitization assays in L1.2 cells stably transfected with hCCR8 and mCCR8. In each experiment a supramaximal dose of agonist was added at 50 s followed by a supramaximal dose of another agonist at 250 s. The hCCR8/L1.2-transfected cells were stimulated with 10-8 M I-309 and 10-8 M vMIP-I . TCA-3 was not used for the hCCR8/L1.2-transfected cells because it did not induce a maximal response. The mCCR8/L1.2-transfected cells were stimulated with 10-7 M I-309, 10-8 M TCA-3, and 10-9 M vMIP-I. One of two representative experiments is shown for the hCCR8/L12-transfected cells and one of three for the mCCR8/L1.2-transfected cells.

 
The two viral chemokines vMIP-II and MC148 were tested in calcium mobilization assays. At concentrations of 100 nM, neither vMIP-II nor MC148 could induce calcium mobilization in the hCCR8/L1.2 or mCCR8/L1.2 cell lines (Fig. 5 ). However, vMIP-II did inhibit the responses mediated through the human as well as the mCCR8 receptor. It is surprising that, whereas MC148 was found to be an efficient blocker of the I-309-mediated response through the hCCR8 receptor, MC148 was unable to block the TCA-3-mediated response through the mCCR8 receptor (Fig. 5) .



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  		Figure 5. Effect of recombinant MC148 and vMIP-II on calcium mobilization on L1.2 cells stably transfected with hCCR8 and mCCR8. MC148 (10-7 M), vMIP-II (10-7 M), or vehicle was added to the cells at 50 s followed by a submaximal dose of 10-9 M I-309 or 10-9 M TCA-3 at 150 s. The height of the response curve with the endogenous ligand was measured, and the heights in the experiments with MC148 and vMIP-II were expressed as percents of the height in the experiment with the vehicle. A representative example of the results from each experiment is shown at the left, whereas the box diagram to the right shows the average inhibition + SE as indicated. Asterisks indicate inhibition, for P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
By testing the viral chemokines vMIP-I, vMIP-II, and MC148 in parallel on the mCCR8 and hCCR8 receptors, we found that MC148, although a high-affinity antagonist for the hCCR8, is not a ligand for the mCCR8. In contrast, vMIP-I acted as a chemokine agonist and vMIP-II as an antagonist on both CCR8 receptors. The finding that TCA-3 does not target the hCCR8, whereas I-309 targets the mCCR8, is in agreement with an earlier study [31 ].

vMIP-I, an agonist for hCCR8 and mCCR8
Earlier reports have shown vMIP-I to be a selective CCR8 agonist [21 22 ]. In this study, we showed that vMIP-I also acts as an agonist on the mCCR8 with potencies in the subnanomolar range comparable with potencies found for the hCCR8.

vMIP-II an antagonist for hCCR8 and mCCR8
We also found that vMIP-II inhibits calcium mobilization through the hCCR8 and mCCR8 receptors expressed in L1.2 cells. This result is in agreement with findings that vMIP-II inhibited calcium mobilization in hCCR8-transfected human embryonic kidney 293 cells and activated human T cells and that vMIP-II blocked I-309-induced chemotaxis of hCCR8-transfected L1.2 cells [22 25 ]. In contrast, another study found that vMIP-II acts as an agonist on hCCR8-transfected Jurkatt cells [32 ]. Besides targeting CCR8, vMIP-II has been found to block responses mediated through CCR1, CCR2, CCR5, CXCR4, XCR1, and CX3CR1 as well as to inhibit responses through CCR3, CCR4, and CXCR3 [24 25 ]. The action of vMIP-II on CCR3 could be dependent on the cellular setting, because vMIP-II has been shown to induce chemotaxis on eosinophils [33 ].

MC148, a selective antagonist for the hCCR8
Previously, we found that MC148 when probed against a panel of 16 individually cloned receptors targeted only CCR8, on which it acted as a high-affinity antagonist [25 ]. With these characteristics, MC148 could be a useful tool to determine the function of CCR8 in the immune system. Here we were surprised to find that MC148 was unable to bind and block signals through the mCCR8, although it bound and blocked responses through the hCCR8 with high affinity. Thus, it appears that murine disease models should not be chosen, if one wants to use MC148 to decipher the role played by CCR8 in the immune system.

What role does CCR8 play in our immune system?
Questions about the role CCR8 plays in our immune system can be answered only indirectly because no studies have reported the use of CCR8 antagonists in animal models or the phenotype of animals deleted for the CCR8 gene. Functional data for I-309 as well as receptor expression data show that CCR8 is found on monocytes [34 , 35 ], Th2 cells [36 , 37 ], natural killer (NK) cells [38 ], and thymocytes [31 , 39 , 40 ]. Furthermore, I-309 is produced when T cells [41 ], monocytes [42 ], human mast cells [43 ], and endothelial cells [44 ] are activated. Thus it seems that cells of different origin can produce I-309 when activated, which attracts cells such as NK cells and monocytes that initiate an immune response. A prominent example to support this notion has been provided by the poxvirus MCV. It is tempting to ascribe the absence of an inflammatory cell infiltrate in MCV lesions [45 46 47 ] to the MCV-encoded CCR8 antagonist MC148, although MCV also encodes other immunomodulating proteins [48 ].

In addition CCR8 has a unique role for thymocytes, as I-309 has been found to protect thymocyte cell lines from dexamethasone-induced apoptosis [49 ]. It could be speculated that the function of vMIP-I is to protect HHV8-infected lymphocytes from apoptosis.

It will be interesting to see whether MC148 can function as an immunosuppressive agent in nonmurine animal disease models.

Received November 17, 2000; accepted March 6, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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