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(Received for publication, October 23, 1996, and in revised form, March 25, 1997)
From the ABSTRACT The tumor necrosis factor receptor (TNFR)
superfamily consists of approximately 10 characterized members of human
proteins. We have identified a new member of the TNFR superfamily, TR2, from a search of an expressed sequence tag data base. cDNA cloning and Northern blot hybridization demonstrated multiple mRNA species, of which a 1.7-kilobase form was most abundant. However, TR2 is encoded
by a single gene which, maps to chromosome 1p36.22-36.3, in the same
region as several other members of the TNFR superfamily. The most
abundant TR2 open reading frame encodes a 283-amino acid single
transmembrane protein with a 36-residue signal sequence, two perfect
and two imperfect TNFR-like cysteine-rich domains, and a short
cytoplasmic tail with some similarity to 4-1BB and CD40. TR2 mRNA
is expressed in multiple human tissues and cell lines and shows a
constitutive and relatively high expression in peripheral blood T
cells, B cells, and monocytes. A TR2-Fc fusion protein inhibited a
mixed lymphocyte reaction-mediated proliferation suggesting that the
receptor and/or its ligand play a role in T cell stimulation.
INTRODUCTION The members of the tumor necrosis factor receptor
(TNFR)1/nerve growth factor receptor (NGFR)
superfamily are characterized by the presence of three to six repeats
of a cysteine-rich motif that consists of approximately 30-40 amino
acids in the extracellular part of the molecule (1). The crystal
structure of TNFR-I complexed with its ligand showed that a
cysteine-rich motif (TNFR domain) was composed of three elongated
strands of residues held together by a twisted ladder of disulfide
bonds (2). These receptors contain a hinge-like region immediately
adjacent to the transmembrane domain, characterized by a lack of
cysteine residues and a high proportion of serine, threonine, and
proline, which are likely to be glycosylated with O-linked
sugars. A cytoplasmic part of these molecules shows limited sequence
similarities, a finding that may be the basis for diverse cellular
signaling. At present, the members identified from human cells include
CD40 (3, 4), 4-1BB (5), OX-40 (6), TNFR-I (7, 8), TNFR-II (9), CD27
(10), Fas (11), NGFR (12), CD30 (13), and LTBR (14). Viral open reading
frames encoding soluble TNFRs have also been identified, such as SFV-T2
(9), Va53 (15), G4RG (16), and crmB (17).
Recent studies have shown that these molecules are involved in diverse
biological activities such as immunoregulation (18, 19), by regulating
cell proliferation (20-22), cell survival (23-25), and cell death
(26-28).
Because of their biological significance and the diverse membership of
this superfamily, we predicted that there would be further members of
the superfamily. By searching an EST data base, we identified a new
member of the TNFR superfamily. We report here the initial
characterization of the molecule called TR2.
MATERIALS AND METHODS An EST cDNA data base, obtained from over 500 different cDNA libraries (29, 30), was screened for sequence
homology with cysteine-rich motif of the TNFR superfamily, using the
blastn and tblastn algorithms (31). One EST was identified in a human T
cell line library, which showed significant sequence identity to
TNFR-II at the amino acid level. This sequence was used to clone the
missing 5 The myeloid and B cell lines studied represent cell
types at different stages of the differentiation pathway. KG1a and PLB 985 (32, 33) were obtained from Phillip Koeffler (UCLA School of
Medicine), BJA-B was from Z Jonak (SmithKline Beecham), and TF 274, a
stromal cell line exhibiting osteoblastic features, was generated from
the bone marrow of a healthy male donor.2
All of the other cell lines were obtained from the American Type Culture Collection (Rockville, MD). Monocytes were prepared by differential centrifugation of peripheral blood mononuclear cells (PBMC) and adhesion to tissue culture dish. CD19+,
CD4+, and CD8+ were isolated from PBMC by
immunomagnetic beads (Dynal, Lake Success, NY). Endothelial cells from
human coronary artery were purchased from Clonetics (San Diego,
CA).
Total RNA of adult tissues
was purchased from CLONTECH or extracted from
primary cells and cell lines with TriReagent (Molecular Research
Center, Inc., Cincinnati, OH). 5-7.5 µg of total RNA was
fractionated in a 1% agarose gel containing formaldehyde, as described
(34), and transferred quantitatively to Zeta-Probe nylon membrane
(Bio-Rad) by vacuum blotting. The blots were prehybridized, hybridized
with 32P-labeled Xhol/EcoRI fragment
of TR2 or OX-40 probe, washed under high stringency conditions, and
exposed to x-ray films.
High molecular weight human DNA was digested with various restriction
enzymes and fractionated in 0.8% agarose gel. The DNA was denatured,
neutralized, and transferred to nylon membrane and hybridized to
32P-labeled TR2 or its variant cDNA.
The in
situ hybridization and FISH detection of TR2 location in human
chromosomes were performed as described previously (35, 36). FISH
signals and the DAPI banding pattern were recorded separately by taking
photographs, and the assignment of the FISH mapping data with
chromosomal bands was achieved by superimposing FISH signals with a
DAPI-banded chromosome (37).
The 5 The TR2-Fc plasmid, linearized with PvuI, was transfected
into NIH 3T3 by the calcium phosphate co-precipitation method. After selection in 400 µg/ml G418, neomycin-resistant colonies were picked
and expanded. Enzyme-linked immunosorbent assay with anti-human IgG1 and Northern analysis with 32P-labeled TR2
probe were used to select for clones that produce high levels of TR2-Fc
in the supernatant. In some experiments, a slightly differently
engineered TR2-Fc produced in Chinese hamster ovary (CHO) cells was
used. The TR2-Fc was purified by protein G chromatography, and the
amino acid sequence of the N terminus was determined by automatic
peptide sequencer (ABI).
The full-length TR2
cDNA was inserted into HindIII-XhoI sites of
pcDNA 3 vector (Invitrogen, San Diego, CA). TNT-coupled
reticulocyte lysate system (Promega) was used to in vitro
transcribe and translate the TR2 cDNA in pcDNA 3. The
35S-labeled reaction product was fractionated on a 5-15%
gradient SDS-polyacrylamide gel, transferred onto an Immobilon membrane (Millipore, Bedford, MA), and exposed to x-ray film.
PBMC were isolated
from three healthy adult volunteers by Ficoll gradient centrifugation
at 400 × g for 30 min. PBMCs were recovered, washed in
RPMI 1640 (Life Technologies, Inc.) supplemented with 10% fetal bovine
serum, 300 µg/ml L-glutamine, and 50 µg/ml gentamycin,
and adjusted to 1 × 106 cells/ml for two donors and
to 2 × 105 cells/ml for the third donor.
Fifty µl of each cell suspension was added to 96-well (round bottom)
plates (Falcon, Franklin Lakes, NJ) together with 50 µl of TR2-Fc,
IL-5R-Fc, anti-CD4 mAb, or control mAb. Plates were incubated at
37 °C in 5% CO2 for 96 h. One µCi of
[3H]methylthymidine (ICN Biomedicals, Costa Mesa, CA) was
then added for an additional 16 h. Cells were harvested, and
radioactivity was counted.
RESULTS AND DISCUSSION Fig.
1a shows the amino acid sequence of TR2
deduced from the longest open reading frame of one of the isolated
cDNAs (HLHA49). Comparison with other sequenced cDNAs and with
ESTs in the data base indicated potential allelic variants that
resulted in amino acid changes at positions 17 (either Arg or Lys) and
41 (either Ser or Phe) of the protein sequence.
The open reading frame encodes 283 amino acids with a calculated
molecular weight of 30,417. The TR2 protein was expected to be a
receptor. Therefore, the potential signal sequence and transmembrane
domain were sought. A hydrophobic stretch of 23 amino acids toward the
C terminus (amino acids 203-225) was assigned as a transmembrane
domain, because it made a potentially single helical span (Fig.
1a), but the signal sequence was less obvious. The potential
ectodomain of TR2 was expressed in NIH 3T3 and CHO cells as a Fc-fusion
protein, and the N-terminal amino acid sequence of the recombinant
TR2-Fc protein was determined in both cases. The N-terminal sequence of
the processed mature TR2 started from amino acid 37, indicating that
the first 36 amino acids constituted the signal sequence (Fig.
1a).
As shown in Fig. 1b, the in vitro translation
product of TR2 cDNA was 32 kDa in molecular size. Since the first
36 amino acids constituted signal sequence, and its calculated
molecular size was ~4 kDa, the molecular size of the protein backbone
of processed TR2 would be approximately 28 kDa. Recently, Montgomery
et al. (39) published a herpesvirus entry mediator (HVEM)
whose cDNA sequence was identical to TR2. They found that the
transfected HVEM cDNA produced a 32-36-kDa protein. Since it is
larger than the in vitro product, this suggests that the
protein is modified posttranslationally. Two potential
asparagine-linked glycosylation sites are located at amino acid
positions 110 and 173, as indicated in Fig. 1a.
Along with the other members of the TNFR family, TR2 contains the
characteristic cysteine-rich motifs that have been shown by x-ray
crystallography (2) to represent a repetitive structural unit. Fig.
1c shows the potential TNFR domain aligned among TR2, TNFR-I, TNFR-II, CD40, and 4-1BB. TR2 contained two perfect TNFR motifs and two imperfect ones.
The TR2 cytoplasmic tail (TR-2 cy) does not contain the death domain
seen in the Fas and TNFR-I intracellular domains, and appears to be
more related to those of CD40cy and 4-1bbcy. Signals through 4-1BB
and CD40 have been shown to be co-stimulatory to T cells and B cells,
respectively (40, 41).
A human tissue RNA blot was used to
determine tissue distribution of TR2 mRNA expression. TR2 mRNA
was detected in several tissues with a relatively high level in the
lung, spleen, and thymus, but was not found in the brain, liver, or
skeletal muscle (Fig. 2a). TR2 was also
expressed in monocytes, CD19+ B cells, and resting or PMA
plus PHA-treated CD4+ or CD8+ T cells. It was
only weakly expressed in bone marrow and endothelial cells (Fig.
2b), although expression was observed in the hematopoietic cell line KG1a. For comparison, the tissue distribution of OX-40, another member of the TNFR superfamily, was examined. Unlike TR2, OX-40
was not detected in the tissues examined and was detected only in
activated T cells and KG1a. Several cell lines were negative for TR2
expression, including TF274 (bone marrow stromal), MG63, TE85
(osteosarcomas), RL 95-2 (endometrial sarcoma), MCF-7, T-47D (breast
cancer cells), BE, HT 29 (colon cancer cells), HTB-11, and IMR-32
(neuroblastomas), although TR2 was found in the rhabdosarcoma HTB-82
(data not shown).
Several cell lines were examined for inducible TR2 expression. HL60,
U937, and THP1, which belong to the myelomonocytic lineage, all
increased TR2 expression in response to the differentiating agents PMA
or Me2SO (Fig. 2c). Increases in expression in
response to these agents were also observed in KG1a and Jurkat cells.
In contrast, PMA did not induce TR2 expression in MG63, but
unexpectedly TNF- In almost all cases, the predominant mRNA was approximately 1.7 kilobases in size, although several higher molecular weight species
could be detected in some tissues (Fig. 2a), and many cDNAs and ESTs that were sequenced contained insertions in the coding region indicative of partial splicing. The abundance of higher
molecular weight mRNAs raises the possibility that TR2 may in part
be regulated at the level of mRNA maturation.
The FISH mapping procedure was
applied to localize the TR2 gene to a specific human chromosomal
region. The assignment of a hybridization signal to the short arm of
chromosome 1 was obtained with the aid of DAP I banding. A total of 10 mitotic figures were photographed, one of which is shown in Fig.
3a. The double fluorescent signals are
indicated on the schematic diagram of chromosome 1 as shown in Fig.
3b. This result indicated that the TR2 gene is located on
the chromosome 1 region p36.2-p36.3. The TR2 position is in close
proximity with CD30 (42), 4-1BB (43, 44), OX-40 (45), and TNFR-II
(46), suggesting that it evolved through a localized gene duplication
event. Interestingly, all of these receptors have stimulatory
phenotypes in T cells in response to cognate ligand binding, in
contrast to Fas and TNFR-I, which stimulate apoptosis. This prompted us
to test if TR2 might be involved in lymphocyte stimulation.
To
determine the potential involvement of cell surface TR2 with its ligand
in lymphocyte proliferation, we examined allogeneic MLR proliferative
responses. As shown in Fig. 4, a and
b, when TR2-Fc was added to the culture, a significant
reduction of maximal responses was observed (p < 0.05). The addition of TR2-Fc at 100 µg/ml inhibited the
proliferation up to 53%. No significant inhibition of proliferation
was observed with the control IL-5R-Fc. Surprisingly, at high
concentrations (10-100 µg/ml) IL-5R-Fc was shown to enhance proliferation. The concentrations of TR2-Fc required to inhibit MLR
proliferation (1-100 µg/ml) are comparable with those of CD40-Fc required for inhibition in other lymphocyte assays (47-50). An anti-CD4 mAb assayed simultaneously inhibited MLR-mediated
proliferation up to 60%, whereas a control anti-IL-5 mAb failed to
inhibit the proliferation. It is well known that a major component of
the MLR proliferative response is T cell-dependent; hence,
it would appear that inhibiting the interaction of TR2 with its ligand prevents optimal T lymphocyte activation and proliferation.
Hence, we have identified an additional member of the TNFR superfamily
that either plays a direct role in T cell stimulation or binds to a
ligand which can stimulate T cell proliferation through one or more
receptors, which may include TR2. We are currently trying to identify
this ligand to which TR2 binds to clarify its role.
FOOTNOTES REFERENCES
Volume 272, Number 22,
Issue of May 30, 1997
pp. 14272-14276
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
§¶,
,
, Zang H
,,,,,,,, and
Department of Microbiology and Immunology
and Walther Oncology Center, Indiana University School of Medicine,
Indianapolis, Indiana 46202, the 
Department of Molecular
Immunology, King of Prussia, Pennsylvania 19406, and ** Human Genome
Sciences, Inc., Rockville, Maryland 20850
end by RACE (rapid amplification of cDNA ends) using a
5-RACE ends-ready cDNA from human leukocytes
(Clontech, Palo Alto, CA). This sequence matched
three further ESTs (HTOBH42, HTOAU65, and HLHA49). Complete sequencing
of these and other cDNAs indicated that they contained an identical
open reading frame homologous to the TNFR superfamily, and it was named
TR2. Analysis of several other ESTs and cDNAs indicated that some
cDNAs had additional sequences inserted into the open reading frame
identified above and might represent various partially spliced
mRNAs.
portion of the TR2 containing the entire putative open reading frame of
extracellular domain was amplified by polymerase chain reaction (38).
For correctly oriented cloning, a HindIII site on the 5 end
of the forward primer and a BglII site on the 5 end of the
reverse primer were created. The Fc portion of human IgG1
was PCR-amplified from ARH-77 (ATCC) cell RNA and cloned in the
SmaI site of the pGem7 vector (Promega, Madison, WI). The Fc
fragment, including hinge, CH2, and CH3 domain
sequences, contained a BglII site at its 5 end and an
XhoI site at its 3 end. The HindIII-BglII fragment of TR2 cDNA was
inserted upstream of human IgG1Fc and an in-frame fusion
was confirmed by sequencing. The TR2-Fc fragment was released by
digesting the plasmid with HindIII-XhoI and
cloned into pcDNA3 expression plasmid.
Fig. 1.
a, deduced amino acid sequence of TR2.
The signal region is underlined. The potential glycosylation
sites are underlined with a heavy line. The
putative transmembrane region is double underlined. The
partial amino acid sequence of recombinant TR2 reads as
PALP ..., which indicates that the first 36 amino acids
constitute a signal sequence. The GenBankTM accession number of this
sequence is U81232[GenBank]. b, in vitro transcription and
translation of TR2 cDNA. TR2 cDNA in pcDNA 3 (lane
1) and reversely oriented TR2 cDNA in pcDNA 3 (lane
2) was used for in vitro translation by the TNT-coupled reticulocyte lysate system (Promega). [35S]Met-labeled
translation product was fractionated by a 5-15% gradient
SDS-polyacrylamide gel electrophoresis. M indicates
molecular size markers, and the arrow indicates TR2 protein
band. c, aligned amino acid sequence of extracellular motif
of TR2 with other TNFR family members. The amino acid sequence of TR2
was aligned with those of TNFR-I, TNFR-II, CD-40, and 4-1BB on the
basis of sequence homology and conserved cysteines.
[View Larger Version of this Image (36K GIF file)]
Fig. 2.
a, Northern blot tissue distribution of
TR2 and OX-40. RNA extracted from Jurkat cells, treated with 50 nM PMA for 48 h, was electrophoresed together with the
tissue samples for comparison. The poly(A+) RNA was
purified from 10 µg of total RNA using Dynabeads oligo(dT) 25. A
photograph of the ethidium bromide-stained 18 S ribosomal RNA is
included to show the RNA loading of the various samples. Under the
electrophoretic conditions used, TR2 (arrow), OX-40, and 18 S ribosomal RNAs have apparent sizes of 1.7, 1.3, and 1.8 kilobases,
respectively. b, Northern blot RNA expression in cell lines
and primary cells. Total RNA was extracted from untreated or cells
treated for 48 h with PMA (10 ng/ml) and PHA (5 µg/ml) and 5 µg of each sample was analyzed. c, Northern blot-induction of RNA expression. KG1a, HL60, U937, THP1, and Jurkat cells were treated with 50 nM PMA or 1.5% Me2SO for
70 h, and total RNA was extracted for analysis. MG63 cells were
treated with 50 nM PMA or 100 ng/ml of TNF
for 7 h.
[View Larger Version of this Image (42K GIF file)]
did.
Fig. 3.
a, combined DAPI banding and in
situ hybridization. Panel A, the position of the TR2
probe is shown by orange dots on a chromosome. Panel
B, the same chromosome with DAPI banding. b,
localization of TR2 on human chromosome. A schematic diagram of human
chromosome 1 is shown, and the positions at which TR2 hybridization
signals were detected are indicated by filled circles.
[View Larger Version of this Image (25K GIF file)]
Fig. 4.
Inhibition of allogenic proliferation by
TR2-Fc. a, effect of TR2-Fc on a three-way MLR. PBMCs were
adjusted to 1 × 106 cells/ml for two donors and to
2 × 105 cells/ml for the third donor. Fifty
microliters of each cell suspension was added to 96-well round bottom
plates, together with 50 µl of TR2-Fc (
) or with 50 µl of
IL-5R-Fc (
). [3H]Methylthymidine incorporation was
measured as an indication of cell proliferation. The error
bars represent standard errors. b, effect of anti-CD4
mAb on a three-way MLR. PBMCs were adjusted to 1 × 106 cells/ml for two donors and to 2 × 105 cells/ml for the third donor. Fifty microliters of each
cell suspension was added to 96-well round bottom plates together with 50 µl of anti-CD4 mAb () or with 50 µl of 2B6 mAb ().
[3H]Methylthymidine incorporation was measured as an
indication of cell proliferation. The error bars represent
standard errors.
[View Larger Version of this Image (18K GIF file)]
§
The first two authors contributed equally to this work.
¶
To whom correspondence should be addressed. Tel.:
317-274-3950; Fax: 317-274-4090; E-mail:
kkwon{at}sunflower.bio.indiana.edu.
Present address: Dept. of Microbiology, Chosun University
School of Dentistry, Kwang Ju 501-759, Korea.
1
The abbreviations used are: TNFR, tumor necrosis
factor receptor; NGFR, nerve growth factor receptor; CHO, Chinese
hamster ovary; DAPI, 4,6-diamidino-2-phenylindole; EST, expressed
sequence tag; FISH, fluorescein in situ hybridization; MLR,
mixed lymphocyte reaction; PBMC, peripheral blood mononuclear cell;
PHA, phytohemagglutinin; PMA, phorbol myristic acetate; RACE, rapid
amplication of cDNA ends; mAb, monoclonal antibody; HVEM,
herpesvirus entry mediator.
2
K. B. Tan and Z. Jonak, unpublished data.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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G. Shi, H. Luo, X. Wan, T. W. Salcedo, J. Zhang, and J. Wu Mouse T cells receive costimulatory signals from LIGHT, a TNF family member Blood, October 16, 2002; 100(9): 3279 - 3286. [Abstract] [Full Text] [PDF]
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ABSTRACT