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Journal of Virology, April 2000, p. 3881-3887, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Induction of a Novel Cellular Homolog of
Interleukin-10, AK155, by Transformation of T Lymphocytes with
Herpesvirus Saimiri
Andrea
Knappe,
Simon
Hör,
Sabine
Wittmann, and
Helmut
Fickenscher*
Institut für Klinische und Molekulare
Virologie, Friedrich-Alexander-Universität
Erlangen-Nürnberg, D-91054 Erlangen, Germany
Received 24 November 1999/Accepted 18 January 2000
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ABSTRACT |
Although herpesvirus saimiri-transformed T lymphocytes retain
multiple normal T-cell functions, only a few changes have been described. By subtractive hybridization, we have isolated a novel cellular gene, ak155, a sequence homolog of the
interleukin-10 gene. Specifically herpesvirus saimiri-transformed T
cells overexpress ak155 and secrete the protein into the
supernatant. In other T-cell lines and in native peripheral blood
cells, but not in B cells, ak155 is transcribed at low
levels. AK155 forms homodimers similarly to interleukin-10. As a
lymphokine, AK155 may contribute to the transformed phenotype of human
T cells after infection by herpesvirus saimiri.
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TEXT |
Human T lymphocytes are transformed
to stable growth in culture after infection with certain subgroup C
strains of herpesvirus saimiri (HVS) (saimiriine herpesvirus type 2), a
T-cell tumor virus of New World monkeys (1). The transformed
human T cells carry multiple nonintegrated viral episomes; they do not
release virions and show only limited virus gene expression (1,
11, 23). In a variety of test systems, HVS-transformed T cells
were shown to retain essential functions of their nontransformed
parental cells (reviewed in references 4, 13, 30,
and 32). In particular, the major histocompatibility
complex-restricted antigen-specific reactivity of parental T-cell
clones was preserved and resulted in increased proliferation, cytokine
release, and cytotoxicity after stimulation (3, 6, 34, 43).
In contrast to multiple reports on preserved functions, little is known
about cellular features which are clearly changed after transformation.
The most pronounced difference is a specific type of hyperreactivity to CD2 stimulation via cell-bound CD58 or cross-linked CD2 antibodies (33). Moreover, unusually high levels of gamma interferon
are produced after stimulation, which shifts transformed T helper 2 cells to the T helper 0 phenotype (6). Finally, the
nonreceptor tyrosine kinase Lyn is aberrantly expressed and
enzymatically active in T cells after HVS transformation (12,
44). Functional consequences of this phenomenon have not yet been defined.
Cloning of ak155 by subtractive hybridization.
In
order to describe the phenotypic T-cell alterations after HVS
transformation in more detail, we applied the technique of subtractive
hybridization for cloning cDNA fragments of transcripts which are
specifically present in transformed human T cells and not in their
untransformed parental cells (23). Using the acidic phenol
extraction method, total cellular RNA was prepared from the phorbol
ester-stimulated transformed cell line 3C (CD8+
[11]) and from nontransformed T cells of the same
donor. cDNA was generated using purified polyadenylated mRNA and
Moloney murine leukemia virus reverse transcriptase (Clontech,
Heidelberg, Germany). The second strand was synthesized by a mixture of
DNA polymerase I, RNase H, Escherichia coli DNA ligase, and
T4 DNA polymerase. Double-stranded cDNA was digested with
RsaI to create small fragments. Specific adapters were
ligated to the cDNA fragments in order to allow subtraction based on
representational difference analysis (PCR-Select; Clontech). Advantage
KlenTaq polymerase (Clontech) was applied for PCR. Subtracted PCR
products were cloned into pCR2.1 (Invitrogen, Groningen, The
Netherlands) and sequenced using M13 reverse and T7 primers with the
dye dideoxy terminator method (ABI, Weiterstadt, Germany). The
resulting library of 399 sequenced plasmids comprised 280 viral and 119 cellular cDNA clones. Among the cellular cDNAs, 28 clones were not yet
represented in the current nucleotide databases (23).
One of these novel cDNA clones, ak155, contained an insert
of 506 bp and displayed weak nucleotide homology to the cellular interleukin-10 (IL-10) gene. Subsequently, the cDNA was completed by 5'
and 3' rapid amplification of cDNA ends (Marathon; Clontech). The
resulting cDNA, of 1076 nucleotides (nt), carried 29 nt as a poly(A)
tail and a polyadenylation signal at position 1027. The cDNA displayed
an open reading frame of 513 nt (position 36 to 549) with coding
capacity for a polypeptide of 171 amino acids (aa) and a predicted
hydrophobic signal sequence of 21 aa. The isoelectric point was
calculated as 10.77. With RNase protection assays, the transcription
initiation site was mapped to nt 60 upstream of the ATG, whereas the
cDNA clones resulting from 5' rapid amplification of cDNA ends started
35 nt upstream of the translation initiation site. The predicted AK155
protein showed 24.7% amino acid identity and 47% amino acid
similarity to human IL-10 (Fig. 1A). The homology values were similar
when AK155 was compared to the human, murine, and bovine IL-10
molecules and to IL-10 of Epstein-Barr virus (EBV). The structural
prediction generated with the Genetics Computer Group program package
indicated a series of six helices and four highly conserved cysteine
residues which are assumed to be relevant for the dimer formation of
IL-10. The structural predictions are supported by experimental data on
the viral IL-10 variant (45).
Chromosomal localization and genomic structure.
Upon further
database searches, we detected a local nucleotide sequence identity of
ak155 to chromosome 12q15 at a genomic sequence-tagged site
(accession no. U29151) used for mapping the genomic region in a 6-Mb
yeast artificial chromosome contig (15, 38). Similarly to
the gamma interferon gene, downstream at a distance of 41 kb,
ak155 is oriented towards the centromere. We obtained the
respective genomic cosmids and plasmid subclones from E. Schoenmakers
(Louvain, Belgium) and determined the exon-intron structure of the gene
(Fig. 1B). The five ak155
exons of 206, 57, 135, 66, and 583 bp are disrupted by three small
introns (85, 159, and 86 bp) and one large intron of more than 23 kb.
We sequenced the 5' and 3' flanking regions, the exons, and the small
introns from the cosmid clones. Recently, the genomic sequence of the respective region of human chromosome 12q15 has become available in
GenBank (accession no. AC007458; 191,111 bp; BAC RPCI11-444B24). Within
this entry of high-throughput genome sequence data, our genomic
sequences correspond to nt 140063 to 141674 (1,612 nt comprising exons
4 and 5 and the 3' region) and 159771 to 166615 (6,839 nt comprising
the promoter region, exons 1 to 3, and a part of intron 3) with a gap
in intron 3. Whereas the exons are strictly conserved in both genomic
sequences, some allelic divergence was observed in the 5' upstream
region (four point mutations and deletion of 3 nt within a region of
395 nt) and within intron 3 (nine point mutations, one insertion of 3 nt, and one deletion of 6 nt within a stretch of 3,635 nt).

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FIG. 1.
Amino acid sequence alignment and genomic structure of
ak155. (A) The amino acid sequences of AK155, human IL-10
(hIL10), and EBV IL-10 (vIL10) were aligned. Identical amino acids are
shaded. Cysteine residues C1 to C4 are conserved. Six predicted helical
areas (helices A to F) for the three proteins are marked. (B) The
genomic exon-intron structure and the ak155 coding region
are depicted. The nucleotide positions above the structure refer to
ak155 cDNA. The nucleotide positions below the structure
correspond to the genomic sequence of the human chromosome 12q15
region.
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Overexpression of ak155 in HVS-transformed
lymphocytes.
In the next step, the expression pattern was studied.
The ak155 cDNA had been cloned from an HVS-transformed human
CD8+ T-cell line (3C, transformed by virus strain C488
[11, 23]). First, we analyzed ak155
transcription by Northern blotting utilizing total cellular RNA and the
coding region as probe DNA. Whereas strong ak155 signals at
a position corresponding to 1.3 kb were readily detectable in T-cell
line 3C, there was no hybridization found with mRNA from the human
T-cell leukemia line Jurkat or from primary T cells after mitogen
stimulation and cultivation in the presence of IL-2. Additional
stimulation with the phorbol ester tetradecanoyl phorbol acetate (TPA)
(2 ng/ml for 6 h) did not induce ak155 transcription
(Fig. 2A). A series of other
HVS-transformed T-cell lines contained ak155 transcripts as
well (Fig. 2B): CB-15, Kesting, and A488.1 (CD4+;
transformed by C488 [1, 11, 12]), P1084 and B488.1
(CD8+; transformed by C488 [1, 12]), and
the C139-transformed T-cell lines A139.1 (
T-cell receptor) and
A139.3 (
, CD4+ [12]). Moreover, we
were able to demonstrate ak155 transcripts in transformed T
cells from New World monkeys (Saguinus oedipus) (T cells
from donors B133 and R226 [24]). Remarkably,
ak155 expression was not specific for the virus subgroup
used for transformation and was similarly detectable in T cells
transformed by the virus strains A11, B-SMHI, and C488 (Fig. 2C).
Additionally, various other cell types were tested for ak155
transcripts by Northern blotting (Jurkat, SupT1, MT2, C91PL, HuT-102,
B/JAB, HeLa, and Tera2 [Fig. 2D]). With this method, we were unable
to identify additional ak155-positive cell types. Infection
of the permissive epithelial cell line OMK with HVS C488 did not induce
ak155 transcription.

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FIG. 2.
ak155 transcription pattern. The
transcription of ak155 was analyzed by Northern blotting (A
to D) and RT-PCR (E and F). (A) Strong ak155 transcript
bands were demonstrated for the HVS-transformed CD8+ human
T-cell line 3C, but not for either nontransformed T cells or Jurkat
cells. Phorbol ester stimulation (TPA; 2 ng/ml for 6 h) did not
affect ak155 transcription. Laminin receptor transcripts are
shown as a control. (B) A series of additional HVS-transformed T-cell
lines also transcribed ak155: CB-15, Kesting, and A488.1
(CD4+; transformed by C488), P1084 and B488.1
(CD8+; transformed by C488), and the C139-transformed
T-cell lines A139.1 ( T-cell receptor) and A139.3 ( ,
CD4+). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
transcripts are shown as a control. (C) ak155 transcripts
were also demonstrated in transformed T cells from New World monkeys
(S. oedipus) (T cells from donors B133 and R226
[24]). ak155 expression was not specific
for the virus subgroup used for transformation and was similarly
detectable in T cells transformed by the virus strains A11, B-SMHI, and
C488. rRNA bands are shown as a transfer control. (D) Various other
cell types were tested by Northern blotting for ak155
transcripts (Jurkat, SupT1, MT2, C91PL, HuT-102, B/JAB, HeLa, and
Tera2). No additional ak155-positive lines were identified.
Infection of the permissive epithelial cell line OMK with HVS C488 did
not induce ak155 transcription. GAPDH transcripts are shown
as a control. (E) By using RT-PCR we confirmed that HVS-transformed
human T-cell lines (CB-15 and 3C) transcribed ak155 at a
high level (540-bp fragment). Transcripts were also detected in T
blasts but at low levels. Additional phorbol ester stimulation did not
change the signal intensity. The cDNA plasmid pAK155 served as a
positive control. (F) Weak RT-PCR signals for ak155
transcripts were detected from unstimulated fresh peripheral blood
mononuclear cells (PBMC) of 10 healthy blood donors by ethidium bromide
staining and confirmed by Southern blot hybridization. -Actin
transcripts are shown as a positive control.
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By using reverse transcription (RT)-PCR with random hexamer primers,
reverse transcriptase (Superscript; Gibco), and the specific
primers
HF123 (GTG-AAC-GGA-AAT-GCT-GGT-G) and HF126
(GGC-TTT-GGT-TTA-CTG-ACT-G),
we confirmed that a large
number of HVS-transformed human T-cell
lines transcribed
ak155 at high levels (540-bp fragment [example
shown in
Fig.
2E]). With a RT-PCR protocol with increased sensitivity
(Superscript II; Gibco), we screened various laboratory cell lines,
mainly of hematopoietic lineages (Table
1) (
31). In addition,
we
tested the same RNA samples for IL-10 and for

-actin transcripts
as
a positive control. The primers HF360
(TCT-CAA-GGG-GCT-GGG-TCA-GCT-ATC-CCA)
and HF361
(ATG-CCC-CAA-GCT-GAG-AAC-CAA-GAC-CCA-GAC) were used
for
demonstrating IL-10 transcripts, and HF291
(CGG-GAA-ATC-GTG-CGT-GAC-AT)
and HF292
(GAA-CTT-TGG-GGG-ATG-CTC-GC) were used for demonstrating

-actin transcripts. The results (Table
1) were monitored in
a simple
semiquantitative way. Strong signals were easily detectable
in ethidium
bromide-stained agarose gels (+++); weak signals were
still detected by
simple ethidium bromide staining (++ [example
in Fig.
2F]), whereas
in some cases, faint signals were detectable
only after Southern blot
hybridization of the same gels (+). In
order to confirm specificity,
all IL-10 gene and
ak155 RT-PCR
gels were analyzed by
Southern blot hybridization. Additionally,
selected PCR product samples
were tested for specificity by direct
sequencing. Whereas the IL-10
gene was transcribed in most cell
lines of the T or B lineage,
ak155 transcription was rather specific
for T cells. A
series of leukemia T-cell lines and human T-cell
leukemia virus
(HTLV)-transformed T-cell lines, as well as primary
mitogen-stimulated
T cells, showed
ak155 transcripts. In contrast,
most other
cell lines tested were negative for
ak155 transcripts.
The
human herpesvirus 8 (HHV-8)-containing cell line BCBL-1 and
the
Hodgkin's lymphoma line L428 harbored small amounts of transcripts
(+). The
ak155 transcript amounts did not seem to depend on
the
level of T-cell activity: phorbol ester stimulation or inhibitory
treatment with cyclosporine did not change the transcript levels
observed. Moreover, unstimulated fresh peripheral blood cells
of 10 healthy blood donors were positive for
ak155 mRNA (++ [Fig.
2F and Table
1]). Thus, we conclude that
ak155 is normally
expressed
by certain T cells at low levels and specifically
overexpressed
by T cells after HVS transformation.
Dimer formation and secretion of AK155 from human T cells.
We
cloned the ak155 open reading frame without the N-terminal
21-aa signal peptide into the bacterial expression vector pQE30 (Qiagen, Hilden, Germany). After
isopropyl-
-D-thiogalactopyranoside (IPTG) induction in
E. coli K-12/M15/pRep4, the recombinant N-terminal histidine-tagged protein was purified under denaturing conditions on
nickel-nitrilotriacetic acid-agarose columns and renatured by dialysis
(Fig. 3A). The denatured recombinant
protein migrated as a 19-kDa band in sodium dodecyl sulfate (SDS) gel
electrophoresis. When the protein was loaded in the absence of
-mercaptoethanol and without heat denaturation, the 19-kDa band
shifted to the 36-kDa position. This is an indication of spontaneous
dimer formation and functional protein folding after renaturation. The
recombinant protein was used to raise polyclonal rabbit antisera.
Moreover, the predicted mature protein coding sequence was fused to a
CD8 leader sequence and N-terminal Flag epitope tag as described for IL-10 (18, 26). This construct was cloned into the
eukaryotic expression vector pME18S under the control of the SR
hybrid promoter (28, 41). After transfection of COS-7 cells,
the recombinant protein was easily detectable by Western blotting
either with an anti-Flag monoclonal antibody (Integra, Fernwald,
Germany) or with rabbit antiserum. The eukaryotically expressed protein efficiently formed dimers when tested under nondenaturing conditions with either of the two antibodies (Fig. 3B). Finally, the endogenous AK155 protein of HVS-transformed human T cells was demonstrated by
Western blotting utilizing rabbit antiserum. AK155 protein was detected
in lysates of the transformed T-cell lines 3C (CD8+) and
CB-15 (CD4+) without previous immunoprecipitation and in
culture supernatants after immunoprecipitation with rabbit antiserum
and protein G-agarose (Roche) (Fig. 3C).

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FIG. 3.
AK155 dimerization and production by HVS-transformed
human T cells. (A) Recombinant amino-terminally histidine-tagged AK155
protein was expressed after induction in E. coli. The
protein was purified by nickel-nitrilotriacetic acid-agarose
chromatography. The denatured recombinant protein was demonstrated as a
19-kDa band in SDS gels. In absence of 2-mercaptoethanol (2ME) and
without heat denaturation, the 19-kDa band shifted to the 36-kDa
position. A Coomassie-stained SDS gel is shown. (B) Recombinant
amino-terminally Flag-tagged AK155 protein was expressed in COS-7 cells
after transfection. The recombinant protein was easily detectable by
Western blotting either with the anti-Flag monoclonal antibody or with
rabbit antiserum. In both cases, the eukaryotically expressed protein
efficiently formed dimers when tested under nondenaturing conditions.
(C) The endogenous AK155 protein from HVS-transformed human T cells (3C
and CB-15) was demonstrated by Western blotting with rabbit antiserum.
Protein was detected in lysates of the transformed T-cell lines 3C and
CB-15 without previous immunoprecipitation and in their supernatants
after immunoprecipitation with rabbit antiserum and protein G-agarose.
As a control, bacterially expressed His-AK155 is shown in the first
lane. Due to the histidine tag, this protein appears at a slightly
larger size than the endogenous protein from 3C and CB-15 cells. AK155
was detectable neither in Jurkat cells nor in their supernatant. The
Western blots were developed with chemiluminescence reactions.
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Although many functional features of parental T-cell clones are
maintained after transformation by HVS, little is known about
functional changes besides CD2 hyperreactivity, aberrant Lyn
expression,
and the tendency towards the T helper 1 phenotype due to
high
levels of gamma interferon (
6,
12,
33,
44). Although
the viral genes
stpC and
tip, which are essential
for transformation,
have been identified and functionally
characterized, it is still
unclear by which mechanism they finally do
cause the transformed
phenotype of T cells (
2,
10,
20,
23; reviewed in references
4 and
21). Using the nonbiased approach of subtractive
hybridization
and representational difference analysis, we have
isolated a novel
cellular gene,
ak155, which is strongly
expressed in HVS-transformed
T cells. Northern blotting analysis
indicated that
ak155 overexpression
is highly specific for
this cell
type.
ak155 has been mapped to the human chromosome 12q15. This
locus is in the vicinity of a chromosomal breakpoint region called
the
multiple-aberration region in benign tumors, such as leiomyomas
of the
uterus, lipomas, and pleomorphic adenomas of the salivary
gland
(
38,
42). A salivary gland adenoma cell line carried
a
complex genomic rearrangement in which the high-mobility-group
protein
HMGIC gene from the 12q15 multiple-aberration region was
inserted into
the large intron of
ak155 (
15). The gamma
interferon
gene is situated downstream of
ak155 at a
distance of approximately
41 kb. Both the gamma interferon gene and
ak155 are overexpressed
in HVS-transformed T cells. Thus, a
common regulatory mechanism
for the two genes is conceivable. In
contrast, the human IL-10
gene is localized to human chromosome 1 (
22). Simple gene duplication
is unlikely, since the
sequence homology is rather low. Although
the overall intron-exon
structure is relatively similar, a large
intron of 23 kb is not found
in the IL-10 genes of various
species.
IL-10 is a multifunctional, pleiotropic cytokine with stimulatory and
suppressive effects on B and T cells (reviewed in references
9,
17, and
35). HVS-transformed
human T-cell lines are
able to produce IL-10 (
29) (Table
1).
IL-10 is the relevant
growth factor for suppressive regulatory T cells
(
16). The IL-10
receptor consists of two chains (
18,
25,
26). The distant
homology of AK155 to IL-10 suggests that use
of the IL-10 receptor
by AK155 is unlikely. Several viruses carry their
own variants
of the IL-10 gene. The IL-10 homologs of EBV
(
19) and equine
herpesvirus type 2 (
37) are much
more homologous (approximately
70% amino acid identity) to IL-10 than
to AK155 (approximately
25% amino acid identity). EBV IL-10 does
engage the IL-10 receptor
(
27). In mice, EBV IL-10 was shown
to inhibit the rejection
of transplanted organs and of allogeneic and
syngeneic tumors
(
36,
39). IL-10 of the orf parapoxvirus
also exhibits some
inhibitory effect on T-cell proliferation
(
14). IL-10 of EBV
has been studied in detail. Although
there are subtle functional
differences between viral and cellular
IL-10 (
27), cellular
IL-10 seems to be functionally dominant
in EBV-transformed B cells
(
5). However, the viral IL-10
gene is dispensable for virus
replication and B-cell transformation by
EBV (
40). Latently
infected EBV-transformed B cells were
shown to express a novel
IL-12 p40-related cytokine, called EBV-induced
gene 3 (
7,
8).
The situation seems to be analogous for HVS,
in which the overexpression
of
ak155 is one of rare changes
between native and transformed
T cells. AK155 is a good candidate to
play a role in the autocrine
growth stimulation leading to spontaneous
proliferation of T cells
after HVS
infection.
Nucleotide sequence accession numbers.
EMBL accession no.
AJ251549 to AJ251551 have been assigned to the cDNA and the genomic
sequences of ak155.
 |
ACKNOWLEDGMENTS |
A. Knappe and S. Hör contributed equally to this work.
We are grateful to K. Moore and Y. Liu (Palo Alto, Calif.) for valuable
experimental advice and for providing reagents, including the
eukaryotic expression vector. We thank E. Schoenmakers (Louvain, Belgium) for genomic cosmids, M. Gramatzki (Erlangen, Germany) for
several hematological tumor cell lines, P. von den Driesch (Erlangen,
Germany) for skin biopsy samples, F. Brière (Dardilly, France)
for stimulating discussions, and B. Fleckenstein (Erlangen, Germany)
for continuous support.
This project was funded by the Deutsche Forschungsgemeinschaft, Bonn,
Germany (Sonderforschungsbereich 466).
 |
FOOTNOTES |
*
Corresponding author. Mailing address: Institut
für Klinische und Molekulare Virologie,
Friedrich-Alexander-Universität Erlangen-Nürnberg,
Schlossgarten 4, D-91054 Erlangen, Germany. Phone: 49-9131-85-23786. Fax: 49-9131-85-26493. E-mail:
fickenscher{at}viro.med.uni-erlangen.de.
Present address: Bavarian Nordic Research Institute GmbH, D-82152
Martinsried, Germany.
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Journal of Virology, April 2000, p. 3881-3887, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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