Microbiol. Immunol.

, 46(3), 135142, 2002

Minireview

The Morbillivirus Receptor SLAM (CD150)

Hironobu Tatsuo, and Yusuke Yanagi*
Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Fukuoka 8128582, Japan
Received December 10, 2001

Abstract: Morbilliviruses are highly contagious pathogens that cause some of the most devastating viral diseases of humans and animals, including measles virus (MV), canine distemper virus (CDV), and rinderpest
virus (RPV). They replicate mainly in lymphoid organs throughout the body and cause severe immunosuppression accompanied with lymphopenia. We have recently shown that human, canine, and bovine signaling lymphocyte activation molecules (SLAMs; also known as CD150) act as cellular receptors for
MV, CDV, and RPV, respectively. In these three morbilliviruses, all strains examined were shown to use
SLAMs of their respective host species, and laboratory strains passaged on SLAM-negative cells were found
to use, besides SLAM, alternative receptors, such as human CD46 for the Edmonston strain of MV. The use
of SLAM as a receptor may be a property common to most, if not all, of the members of morbilliviruses.
Human SLAM is a membrane glycoprotein selectively expressed on the cells of the immune system
(immature thymocytes, activated lymphocytes, activated monocytes, and mature dendritic cells) and
seems to mediate lymphocyte activation and to control interferon- production. The destruction and/or
impairment of infected SLAM-positive cells may be a mechanism for the immunosuppression induced by
morbilliviruses, but other mechanisms may be also involved.
Key words: SLAM (CD150), Morbillivirus, Measles, Canine distemper, Rinderpest

Lake Baikal (44), in lions in Serengeti National Parks

(31), and in leopards and other large cats in zoos (1) have
underscored the ability of CDV to invade new host
species. PRV infects cattle and other ruminants, causing
rinderpest (also known as cattle plague), one of the oldest recorded plagues of livestock and remains a cause of
great economic loss in Africa, the Middle East, and
parts of Asia. Domestic pigs can develop clinical signs
and are regarded as important virus reservoirs in Asia
(26).
All these viruses are highly contagious pathogens
that can be transmitted via aerosol droplets. The devastating acute diseases found in the hosts infected with
these viruses are not identical, but they have important
pathological features in common. All these viruses
mainly replicate in lymphoid organs throughout the
body (lymph nodes and the spleen as well as the thymus
and bone marrows in some cases) during incubation
periods, followed by a sudden onset of systemic dis-

Introduction
Morbilliviruses are enveloped viruses with nonsegmented negative-strand RNA genomes and constitute a
genus within the family Paramyxoviridae. They include
measles virus (MV), canine distemper virus (CDV),
rinderpest virus (RPV), and several other viruses listed in
Fig. 1. MV causes human measles, which used to be one
of the most common childhood diseases before the introduction of live vaccines. It is, however, still a major killer
of children in developing countries, especially in Africa,
claiming more than one million lives per year. MV also
causes subacute sclerosing panencephalitis (SSPE), a
rare (approximately one in a million cases of measles)
late complication of the central nervous system occurring
several years after acute infection (11).
CDV causes distemper, the most important viral disease of dogs with high morbidity and mortality (26).
It infects dogs and related species such as weasels and
raccoons. The recent outbreaks of distemper in seals in

Abbreviations: CDV, canine distemper virus; CPE, cytopathic

effects; EBV, Epstein-Barr virus; mAb, monoclonal antibody; MV,
measles virus; PBMC, peripheral blood mononuclear cells; RPV,
rinderpest virus; SAP, SLAM-associated protein; SLAM, signaling lymphocyte activation molecule; SSPE, subacute sclerosing panencephalitis.

*Address correspondence to Dr. Yusuke Yanagi, Department of

Virology, Faculty of Medicine, Kyushu University, 311 Maidashi,
Higashi-ku, Fukuoka, Fukuoka 8128582, Japan. Fax:8192
6426140. E-mail: yyanagi@virology.med.kyushu-u.ac.jp

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H. TATSUO AND Y. YANAGI

Fig. 1. Phylogenetic relationship among morbilliviruses.

ease accompanied with lymphopenia. Severe immunosuppression is observed during and after the diseases, and
secondary infections are the major cause of death in the
hosts (11, 26).
We have recently shown that a membrane glycoprotein
signaling lymphocyte activation molecule (SLAM; also
known as CD150) is a cellular receptor for MV (41).
Human SLAM is selectively expressed on lymphoid
tissues, explaining the tissue tropism of MV. We have
also shown that dogs and cattle have the molecules
homologous to human SLAM, which act as cellular
receptors for CDV and RPV, respectively (42). In this
review, we will summarize our current knowledge about
SLAM, especially with respect to morbillivirus infections.
Structure and Function of SLAM (CD150)
Human SLAM was originally identified as a cell surface molecule of 7095 kDa recognized by two monoclonal antibodies (mAbs) that were raised against activated B cells (IPO-3) (36) or T cells (A12) (8). cDNA
cloning revealed that human SLAM is a type I membrane
protein with eight potential N-glycosylation sites and
belongs to the immunoglobulin superfamily with one
V domain and one C2 domain (8) (Figs. 2 and 3).
SLAM is classified as a member of the CD2 family
(39). Two disulfide bonds were predicted to exist in
the C2 domain. In its cytoplasmic tail are three unique
tyrosine-based motifs with the consensus sequence
TxYxxV/I/A, which are binding sites for SH2 domaincontaining proteins such as SLAM-associated protein
(SAP; also known as SH2D1A) (34). Alternate splicing
produces a soluble form lacking the transmembrane
domain and a variant membrane form lacking the two
distal tyrosine-based motifs in the cytoplasmic tail,
although in vivo relevance of these forms is currently
unknown (30). The gene encoding SLAM exists in the
human chromosome 1q22-q23, where there is a gene
cluster containing the six genes coding for homologous
molecules, SLAM (CD150), CD84, CD229 (Ly9),
CD244 (2B4), CD48, and 19A (CS1/CRACC). CD84,

Fig. 2. The structure of human SLAM.

CD229, and CD244 are also known to bind SAP (46).

Murine orthologue of human SLAM has been reported and characterized (6). We have also reported the
predicted amino acid sequences of canine, bovine, and
marmoset (cotton-top-tammarin) orthologues (Fig. 3,
Table 1) (41, 42). The tissue distribution and function
has been thus far studied only for human and murine
SLAMs.
SLAM is constitutively expressed on immature thymocytes, CD45ROhigh memory T cells, and a proportion
of B cells and is rapidly induced on peripheral T and B
cells following activation (2, 8, 36). It is not detected on
immature dendritic cells, granulocytes, monocytes, red
blood cells, or platelets (32). However, it is induced on
mature dendritic cells after activation with CD40L or IL1 and on monocytes after activation with LPS or TNF (5, 19, 25, 32). In nonlymphoid organs (the small
intestine, kidney, brain, and heart), the mRNA of SLAM
was not detected by the use of the RT-PCR method (8).
The physiological function of SLAM is still a subject
under intensive study. SLAM was reported to act as a
ligand for itself (30). In B cells, the ligation of SLAM
with mAb IPO-3 was found to augment cell proliferation
induced by anti-CD40 mAb and IL-4 (36). Soluble and
membrane-bound forms of SLAM induced proliferation and immunoglobulin synthesis by activated human
B cells, but mAb A12 did not act as a surrogate SLAM
ligand for B cells (30). IPO-3-induced signal was also
reported to augment CD95-mediated apoptosis (24).
On the other hand, it was reported that the engagement of
SLAM on T cell clones with A12 induced T cell expansion and Th0/Th1 cytokine profile, including the production of IFN- (2, 8). However, a recent study by
Latour et al. reported that SLAM signaling might be

Fig. 3. Predicted amino acid sequences of SLAM of five different species. Marmoset indicates SLAM of cotton-top-tammarin expressed on B95a cells. Amino acid residues having similarity among them are shaded (identical residues: dark; conservative changes: light). The predicted signal peptides of respective SLAMs and the transmembrane
domain of human SLAM are underlined. Potential N-linked glycosylation sites are circled. Four cysteine residues predicted to make two disulfide bonds of the C2 domain are indicated by an asterisk (*). Tyrosine-based signaling motifs in the intracellular domain are boxed. Spaces, indicated by , are introduced for optimal comparison.

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H. TATSUO AND Y. YANAGI

Table 1. Amino acid identity between SLAMs of different

species

Dog
Cow
Human
Marmoset

Cow

Human

Marmoset

Mouse

69

65
65

63
63
86

57
57
62
60

The percentages of identical amino acid residues between

SLAMs of different species are shown.

involved in inhibiting IFN- production by T cells (20).

They interpreted the previous studies so that the effect of
A12 was not agonistic but inhibitory on SLAM function,
either by blocking the binding of SLAM to its ligand or
by functionally sequestering it (20). They also proposed a model for the signal transduction in T cells
induced through SLAM, which involves SAP, FynT (an
isoform of Fyn found only in T cells), and SHIP (SH2domain-containing inositol phosphatase) (20). According to their model, SAP is necessary for the signaling
through SLAM. Mutations of the human SAP gene
cause X-linked lymphoproliferative disease, patients
with which show progressive lymphocyte expansions
after primary Epstein-Barr virus (EBV) infection (34).
Recent studies revealed that SAP-deficient mice have
increased IFN- secretions and deficient IgE productions at the baseline as well as after infections with various microbes (47).
Previous Studies of Morbillivirus Receptors
The Edmonston strain of MV was first isolated by the
use of primary human kidney cells by Enders and Peebles
in 1954. It was further passaged on human kidney cells,
human amnion cells, and/or Vero cells (African green
monkey kidney cell line) and has been widely used in
many laboratories. It was also adapted to chicken
embryo fibroblasts for use as attenuated live vaccines.
Thereafter, Vero cells were usually used to isolate MV
from clinical specimens, although blind passage was
usually required before the development of cytopathic
effects (CPE) (11).
The Onderstepoort strain of CDV was derived from
the virus, which had been isolated from a natural case of
distemper and serially passaged in ferrets. This ferretpassaged virus was then adapted to chicken embryos.
The Onderstepoort strain is now commonly passaged
on Vero cells (7). Several RPV strains were originally
passaged in cattle (or rabbits following adaptation) in
vivo, but some were then adapted to Vero cells or chicken embryos.
It should be noted that all these cells used for mor-

billivirus isolation and passage do not express SLAM.

Studies have reported that these laboratory strains may
have lost virulence to the hosts (13, 15). These strains
were found to infect many types of cells. For example,
the Edmonston and Vero cell-isolated strains of MV
grow well and cause CPE on almost any human and
monkey cell lines.
In 1990, Kobune et al. reported that B95a, an EBVtransformed marmoset B cell line, is highly sensitive
to MV from clinical specimens (17). By the use of
B95a cells, CPE may be found within 24 hr after inoculation with throat swabs or blood from MV patients.
Furthermore, the B95a-isolated strains were shown to
retain virulence to experimentally infected monkeys
(17). In tissue culture, these strains grow well and cause
CPE on B95a cells, but not on most human and monkey
cell lines, including Vero cells. We found that they can
cause CPE on stimulated human peripheral blood
mononuclear cells (PBMC) and on some human lymphocytic cell lines, besides B95a (37, 40). These observations suggested to us that wild type viruses in the
body of measles patients are capable of infecting only
some lymphocytic cell lines, including B95a cells, and
that the laboratory strains were adapted to Vero cells
or other human cells during in vitro passages. We now
know that B95a cells express a high level of marmoset
SLAM (41).
In 1993, it was reported that the laboratory strains of
MV, the Edmonston and Halle strains, use the human
CD46 molecule as a cellular receptor (9, 27). CD46 is a
complement regulatory protein expressed on all human
cells except red blood cells. The distribution of CD46
was consistent with cell tropism of those laboratory
strains, but not with that of B95a-isolated wild type
strains. The infection of cells with wild type strains did
not cause a downregulation of CD46, unlike that with
laboratory strains. Furthermore, several studies showed
that envelope proteins of wild type strains did not
interact with CD46, but that they did with an unidentified
molecule(s) selectively expressed on some lymphocytic
cells, including B95a cells (4, 14, 21, 37, 40).
Stimulated canine peripheral blood lymphocytes and
macrophages were known to be sensitive host cells for
isolation of CDV (23, 26). Moreover, the CDV strain
passaged in dogs in vivo has been studied as a wild
type strain (7). These viruses retain virulence to dogs,
but they do not readily infect Vero cells. However, the
cellular receptor for CDV has been mainly studied by the
use of Vero-adapted strains of CDV. Human CD9 had
been implicated in infections with Vero-adapted CDV
strains, although it was later found that CD9 acted at cellcell fusion, but not at virus-cell fusion (35). B95a was
found to be a sensitive host for CDV and RPV, and

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B95a-isolated CDV strains retain virulence to dogs.

The L strain of RPV is a lapinized virus that has been
passaged on rabbits in vivo and has virulence to them.
B95a is the only host cell system available for the propagation of the L strain, and the propagation of the virus
in B95a cells preserves its pathogenicity for rabbits (18).
A Theileria parva-transformed bovine leukocyte cell
line was also reported to be sensitive to RPV (33). It is
not known whether this cell line expresses bovine SLAM.
Morbilliviruses Use SLAMs as Cellular Receptors
By using expression cloning, we have recently identified human SLAM as a cellular receptor for MV (41).
CHO (Chinese hamster ovary) cells are not susceptible to
MV. The transfection of CHO cells with a human
SLAM cDNA significantly increased the binding of MV
to the cells. An analysis with vesicular stomatitis virus
pseudotypes revealed that virus entry using MV envelope
proteins was highly increased in SLAM-expressing CHO
cells, as compared with that in CHO cells. Furthermore, SLAM-expressing CHO cells developed strong
CPE after MV infection, which was completely blocked
by anti-SLAM mAb IPO-3. These findings were
observed for B95a-isolated strains, PBMC isolated
strains, and the Edmonston strain, indicating that SLAM
is an MV receptor not only for B95a- or PBMC-isolated
wild type strains, but also for the Edmonston strain,
which can apparently use both CD46 and SLAM as
receptors. Because the Edmonston strain has been grown
on SLAM-negative cells, it should not have adapted to
SLAM in vitro, and therefore the precursor of this strain
must have been using SLAM as a receptor in the original
patient from which it was isolated in the 1950s.
We also demonstrated that CDV and RPV respectively use canine and bovine SLAMs as cellular receptors
(42). We used two B95a-isolated CDV strains and the
Onderstepoort strain for our study. CHO cells infected
with these three CDV strains did not develop CPE.
(There are substrains of the Onderstepoort strain (45),
some of which have been known to cause CPE in CHO
cells.) B95a-isolated strains caused CPE in B95a cells,
but not in Vero cells, whereas the Onderstepoort strain
caused CPE in Vero cells, but not in B95a cells. The
development of CPE in B95a cells infected with B95aisolated strains was completely blocked by IPO-3. CHO
cells transfected with a canine SLAM cDNA developed
strong CPE when infected with all these CDV strains.
We studied the Ako vaccine strain of RPV, which had
been highly adapted to cultured cells, grew well, and
caused CPE in many cell lines. Although CHO cells also
developed CPE when infected with the Ako strain of
RPV, CHO cells transfected with a bovine SLAM cDNA

139

developed more extensive CPE. Studies of virus entry

using vesicular stomatitis virus pseudotypes bearing
CDV or RPV envelope proteins also confirmed these
findings.
Thus all morbillivirus strains examined were found to
use SLAMs of their respective host species as cellular
receptors. Laboratory strains, which have been passaged on SLAM-negative cells, can also use alternative
receptors: CD46 for the Edmonston strain of MV and an
unidentified molecule(s) on Vero cells for the Onderstepoort strain of CDV. The Edmonston vaccine strain
must be using another receptor(s) present on chicken
embryo fibroblasts. The Ako strain of RPV also seems
to use a ubiquitously expressed molecule(s), besides
bovine SLAM. We have not had a chance to test wild
type RPV strains passaged on SLAM-expressing cells
(such as B95a) because of biohazard regulations. Furthermore, we have shown that most MV, CDV, and RPV
strains examined could use SLAMs of nonhost species
(human, canine, and bovine) as receptors, although at a
reduced efficiency. Despite sequence differences, the
structure required for the interaction with morbillivirus
envelope proteins may be well conserved among SLAMs
of many different species. This consideration should be
taken into account when MV eradication is planned
because other morbilliviruses may infect humans lacking
sufficient anti-MV immunity. In the case of MV, the V
domain of human SLAM was shown to be sufficient
for its function as an MV receptor (29). On the other
hand, murine SLAM hardly acted as a receptor for MV
or CDV (29 and our unpublished results).
It is thought that when cattle were domesticated, they
passed a progenitor to the modern RPV to humans,
which eventually evolved into MV. Similarly, carnivores could have contracted a morbillivirus infection
from their ruminant prey, which then evolved into CDV
(Fig. 1) (3). MV and RPV are closely related, and CDV
is the most distantly related to MV and RPV among
morbilliviruses. Thus the finding that the three morbilliviruses use SLAMs as cellular receptors suggests that
the usage of SLAM as a receptor has been maintained
from the ancestral virus, accounting for an essential part
of the pathogenesis of morbillivirus infections. We predict that most, if not all, members of morbilliviruses
use SLAMs of their respective host species as cellular
receptors.
SLAM in Morbillivirus Infections
We showed that CHO cells transfected with a human
SLAM cDNA developed syncytia within 36 hr after
inoculation with throat swabs from MV patients (41). By
using plaque assay, we also found that throat swabs

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H. TATSUO AND Y. YANAGI

from measles patients produced many thousands of

plaques on Vero cells transfected with a human SLAM
cDNA or on B95a cells, but no plaque on Vero cells.
These findings indicate that viruses in the throats of
measles patients can use SLAM as a receptor, but cannot
use alternative receptor(s) (including CD46) capable of
producing CPE on Vero cells (28). It is thought that MV
infection is initially established in the respiratory tract
with viral replication in epithelial cells, followed by
extension to local lymphoid tissues (11). Epithelial
cells, however, do not express SLAM. Our interpretation
of this paradox is that the primary targets of MV are not
epithelial cells, but SLAM-expressing cells such as lymphocytes, macrophages, and dendritic cells in lymphoid
tissues of the upper respiratory tract.
Infection with CDV and RPV may occur similarly in
lymphoid tissues. CDV infection often causes encephalitis in dogs, in which CDV-infected macrophages are
thought to invade the central nervous system (43). RPV
infection may lead to severe bloody diarrhea, and mesenteric lymph nodes and gut-associated lymphoid tissues
are major sites of viral replication (26). Many histological studies have indicated the presence of morbillivirus
(MV, CDV, and RPV) antigens in epithelial cells of respiratory, urogenital, and alimentary tracts (11, 26). CDV
antigens are also found in astrocytes in the brains of
CDV-infected dogs (43). Although the distribution of
SLAM has not been studied in dogs and cattle, these findings may indicate that SLAM is not absolutely essential
for morbillivirus entry. Our interpretation is that although
the principal cellular receptors are SLAMs, morbilliviruses can also infect SLAM-negative cells with a
very low efficiency. Even if this is so, questions remain.
Is the specific receptor(s) used to infect SLAM-negative
cells? If it is, is it the same as the alternative receptor(s)
used in cultured cells? Do all virus particles have the
weak ability to enter SLAM-negative cells, or do only
some virus particles that have mutated in the body
acquire the ability?
Morbilliviruses have a high mutation rate because of
the nature of RNA genomes and can easily adapt to use
an alternative receptor(s) in vitro. It was shown that
single amino acid changes in the H protein of MV
enabled B cell-isolated wild type strains to interact
with CD46 (14, 21). Because SLAM-positive cells are a
minor population in the body, some selective pressure
that prevents viruses from adapting to alternative receptor(s) must operate in vivo. Neurons are infected in
SSPE, in which free viruses are rarely produced, and
infection develops very slowly by cell-cell fusion. The
genomes of MV isolated from patients with SSPE have
many mutations. The receptor involved in cell-cell
fusion by SSPE viruses may not be SLAM.

Morbillivirus-induced immunosuppression is of great

interest. Several mechanisms underlying MV-induced
immunosuppression have been proposed, including
impaired or negative signaling to T cells by antigenpresenting cells; secretion of soluble inhibitory factors;
inhibition of lymphocyte proliferation in a specific stage
of the cell cycle; and lymphocyte apoptosis (11, 22).
Although CD46 cross-linking by MV was reported to
inhibit IL-12 production by antigen-presenting cells
(16), it must be tested by the use of wild type MV
strains that have little or no ability to interact with CD46.
Now that SLAM is identified as the cellular receptor
for morbilliviruses, the selective destruction and/or an
impairment of infected SLAM-expressing cells may be
considered one mechanism for the immunosuppression.
Since SLAM is expressed on mature dendritic cells and
activated monocytes, the function of antigen-presenting cells may be affected by MV infection. It is also possible that by interacting with SLAM, MV envelope proteins expressed on MV-infected cells or on MV particles
may affect the signal transduction induced via SLAM in
adjacent cells. The Th2 polarization of cytokine production observed during and after MV infection (12)
may result from the modification of SLAM signaling by
MV. It is also found that SLAM is down-regulated in the
cells infected with MV or coming in contact with MV
envelope proteins (10, 38). Such contact was reported to
cause proliferative unresponsiveness of lymphocytes,
in which Akt kinase was suppressed. This unresponsiveness was also found in SLAM-negative cells, and
reported to be independent of SLAM signaling (10).
All these mechanisms are not necessarily mutually exclusive and may operate together to cause the profound
immunosuppression induced by morbilliviruses.
Conclusion
The identification of SLAM as morbillivirus receptors
has helped us better understand the pathogenesis of
morbillivirus infections as well as the differences in cell
tropism between virus strains. It has also provided the
useful clue to clarify the mechanism for immunosuppression and lymphopenia observed in morbillivirus
infections. The development of drugs disrupting the
interaction between the viruses and SLAM may prove to
be of clinical value to treat and control morbillivirus
infections, complementing currently used live vaccines.
Furthermore, a SLAM transgenic mouse under development is expected to serve as a useful animal model for
morbillivirus infections.

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