Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
* Author for correspondence (e-mail: kikutani{at}ragtime.biken.osaka-u.ac.jp)
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Summary |
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Key words: Sema4D/CD100, Sema4A, CD72, Tim-2, Plexin
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Introduction |
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Sema4D/CD100 |
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Receptor
Two receptor families, the neuropilins and plexins, mediate many semaphorin
functions, such as axonal growth cone collapse
(He and Tessier-Lavigne, 1997;
Kolodkin et al., 1997
;
Comeau et al., 1998
;
Winberg et al., 1998
;
Takahashi et al., 1999
;
Tamagnone et al., 1999
).
Sema4D uses two receptors, plexin-B1 and CD72, which are expressed in
non-lymphoid and lymphoid tissues
(Kumanogoh and Kikutani,
2001
).
Plexin-B1
Plexin-B1, expressed at high levels in the fetal brain and kidney
(Maestrini et al., 1996),
demonstrates a high affinity
(Kd=
1x10-9 M) for Sema4D
(Tamagnone et al., 1999
;
Kumanogoh et al., 2000
). Human
Sema4D stimulation enhances the interaction of the plexin-B1 cytoplasmic
region with the small GTPase Rac1 (Vikis
et al., 2000
). Binding of Sema4D to plexin-B1 also activates the
Rho guanine-nucleotide-exchange factor PDZ-RhoGEF/LARG, leading to RhoA
activation (Swiercz et al.,
2002
). In human epithelial cells, plexin-B1 forms a functional
receptor complex with Met, the tyrosine kinase receptor for scatter
factor-1/hepatocyte growth factor receptor
(Giordano et al., 2002
).
Binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase
activity of Met, leading to the phosphorylation of both the receptor and the
Met substrate Gab1 (Fig. 3).
Interestingly, Artigiani et al. have recently reported that the extracellular
domain of plexin-B1 can be cleaved and modulates the effects of Sema4D
(Artigiani et al., 2003
).
However, it still remains to be determined whether Sema4D can signal through
plexin-B1 in the immune system.
|
CD72
Sema4D utilizes CD72 as its major receptor in lymphoid tissues
(Kumanogoh et al., 2000;
Kumanogoh and Kikutani, 2001
;
Kikutani and Kumanogoh, 2003
;
Suzuki et al., 2003
). CD72
expression is detectable throughout B cell differentiation from early
progenitors to mature B cells (Nakayama et
al., 1989
; Von Hoegen et al.,
1990
; Gordon,
1994
). Expression is downregulated, however, upon terminal
differentiation into plasma cells. CD72 is expressed by professional APCs,
such as macrophages and DCs (Tutt Landolfi
and Parnes, 1997
; Kumanogoh et
al., 2002b
). Several lines of evidence demonstrate that CD72 is
the lymphocyte receptor for Sema4D
(Kumanogoh et al., 2000
):
recombinant soluble Sema4D binds specifically to CD72-expressing
transfectants; antibodies specific for CD72 block the binding of soluble
Sema4D to B cells; and soluble mouse Sema4D fails to stimulate CD72-deficient
B cells, owing to a lack of surface binding. A direct protein-protein
interaction between mouse recombinant soluble Sema4D and CD72 can be detected
by surface plasmon resonance. CD72, a member of the C-type lectin family, is
thought to function as a negative regulator of B cell responses by recruiting
SHP-1, a tyrosine phophatase, to an immunoreceptor tyrosine-based inhibitory
motif (ITIM) in its cytoplasmic region
(Adachi et al., 1998
). In
support of this, B cells from CD72-deficient mice are hyper-proliferative in
response to various stimuli (Pan et al.,
1999
). Both agonistic anti-mouse CD72 monoclonal antibodies and
soluble mouse Sema4D protein can induce dephosphorylation of mouse CD72,
facilitating the dissociation of SHP-1 from CD72
(Wu et al., 1998
;
Kumanogoh et al., 2000
). Thus,
it appears that Sema4D binding turns off inhibitory signaling by CD72
(Kumanogoh et al., 2000
;
Kumanogoh and Kikutani, 2001
)
(Fig. 3).
Biological activities and physiological roles of Sema4D
The expression patterns of Sema4D and its high-affinity receptor,
plexin-B1, imply a role in axonal guidance. In Drosophila, plexin-B
controls the axonal guidance of certain motor neurons by enhancing Rho
signaling (Hu et al., 2001).
Sema4D binding to plexin-B1 results in RhoA activation by regulating
PDZ-RhoGEF/LARG, the GEF responsible for Sema4D-induced growth cone collapse
in primary hippocampal neurons (Swiercz et
al., 2002
). In addition, Sema4D triggers the invasive growth of
epithelial cells, including cell-cell dissociation, anchorage-independent
growth, and branching morphogenesis by binding to the plexin-B1-Met complex
(Giordano et al., 2002
). The
physiological relevance of the above biological activities of Sema4D remains
to be clarified, because no apparent phenotypes in nonlymphoid organs have yet
been observed in Sema4D-deficient mice
(Shi et al., 2000
). Some of
Sema4D functions might be of course compensated for by other semaphorin
molecules in those mice.
A number of biological activities of Sema4D in the immune system have been
reported, and some of these have been confirmed by analysis of
Sema4D-deficient mice (Shi et al.,
2000). Sema4D-expressing CHO cell transfectants promote the in
vitro aggregation and survival of B cells
(Hall et al., 1996
). Human
Sema4D stimulation also induces shedding of CD23 (a low affinity receptor for
IgE, which is used as an activation marker for B cells) from the surface of B
cells (Hall et al., 1996
).
Sema4D-expressing CHO cell transfectants or the addition of soluble
recombinant mouse Sema4D can enhance CD40-induced proliferation and
immunoglobulin production in mouse B cells
(Kumanogoh et al., 2000
).
Similarly, B cell responses to CD40 or LPS stimulation in vitro and humoral
immune responses against T-cell-dependent antigens in vivo are impaired in
Sema4D-deficient mice (Shi et al.,
2000
). Sema4D also plays a role in the activation and maturation
of DCs (Kumanogoh et al.,
2002b
): soluble recombinant Sema4D can enhance CD40-induced DC
maturation, as measured by upregulation of CD40 and CD80, and enhanced
production of interleukin 12. In Sema4D-deficeint mice, T cell priming, in
which DCs play a central role, is severely impaired
(Shi et al., 2000
). Sema4D
also seems to play a role in monocytes and macrophages: soluble human Sema4D
inhibits the spontaneous and MCP-3-induced migration of freshly isolated
monocytes and monocytic cell lines
(Delaire et al., 2001
). We
have also demonstrated that both recombinant soluble human Sema4D and
agonistic anti-huma-CD72 monoclonal antibodies induce the production of
proinflammatory cytokines, such as IL-6 and IL-8, by human monocytes
(Ishida et al., 2003
).
Collectively, these findings suggest that Sema4D has a crucial function in a
broad range of tissues.
By contrast, some reports suggest a possible function for Sema4D as an
immune receptor. Antibody crosslinking of human Sema4D enhances T cell
proliferation in the presence of submitogenic doses of either monoclonal
antibodies against CD3 (a component of the T cell receptor complex) or
monoclonal antibodies against CD2 [a T cell surface antigen that interacts
with LFA-3 (CD58)] (Bougeret et al.,
1992; Herold et al.,
1995
). In human T cells, Sema4D is associated with an unidentified
serine/threonine kinase and a protein tyrosine phosphatase (PTP), CD45
(Elhabazi et al., 1997
;
Herold et al., 1996
). A switch
at the terminal stage of B cell differentiation in the type of PTP activity
associated with human Sema4D has also been reported
(Billard et al., 2000
).
A Drosophila transmembrane semaphorin, Sema-1a, plays a role in
axon guidance, acting through the plexin-A receptor
(Winberg et al., 1998).
However, it might also have a bi-directional role as both a ligand and a
receptor in central synapse formation in Drosophila
(Yu et al., 1998
). This
paradigm supports the plausibility of a bi-directional function for Sema4D. In
what situations might Sema4D function as a receptor? Transfectants expressing
human plexin-B1 sustain the proliferation of normal and leukemic
CD5+ B cells, both of which express human Sema4D
(Granziero et al., 2003
).
These data suggest that human Sema4D can function as a receptor for human
plexin-B1. It remains to be clarified whether the cytoplasmic region of Sema4D
is involved in physiological or pathological roles during the growth of normal
or leukemic CD5+ B cells, respectively, in vivo.
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Sema4A |
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Tim-2 as a Sema4A receptor
Whereas Sema4D binds plexin-B1, the binding of Sema4A to plexins remains to
be investigated. In the immune system, Sema4A-binding partners exist on the
surface of activated T cells but not on B cells and DCs. The binding of Sema4A
to the cell surface of a subset of T cell lines, such as EL-4 cells, is also
observed. Expression cloning using human IgG1-Fc portion-conjugated Sema4A
(Sema4A-Fc) revealed that the Sema4A receptor is a member of the T cell,
immunoglobulin and mucin domain proteins (TIM) family, Tim-2
(Kumanogoh et al., 2002a)
(Fig. 4) - a 305-residue
transmembrane protein. Sema4A-Fc binds COS7 cells transfected with Tim-2 cDNA
in a specific manner (Kumanogoh et al.,
2002a
) and stimulation of cells with Sema4A induces Tim-2 tyrosine
phosphorylation.
|
The Tim family of proteins is expressed on T cells and characterized by a
conserved set of immunoglobulin and mucin domains. McIntire et al. originally
identified a locus conferring susceptibility to mouse allergen-induced airway
hypersensitivity, which they dubbed T cell and airway phenotype regulator
(Tapr) (McIntire et al.,
2001). Subsequent positional cloning revealed this locus to
contain a new family of genes, the Tims. There are remarkable numbers
of Tim-1 sequence polymorphisms within both Tapr and human
Tim-1 (hHAVcr-1) (McIntire et
al., 2001
). The human homologue of Tim-2 has not yet been
identified. Kuchroo and colleagues independently identified Tim-3 in a screen
for Th1 (a functional T cell subset that preferentially produces IFN-
but not IL-4 and plays crucial roles in cell-mediated immunity)-reactive
monoclonal antibodies as a Th1 cell-specific surface protein
(Monney et al., 2002
).
Administration of anti-Tim-3 monoclonal antibodies promotes the development of
EAE, a Th1-dependent autoimmune disease. This result suggests that Tim-3 is
involved in the interactions between Th1 cells and macrophages, which results
in the expansion and activation of macrophages. The fact that both Tim-1 and
Tim-3 play a role in T-cell-mediated immune responses underscores the
functional relevance of Tim-2, a member of the Tim family, in T cell function.
Although the natural ligands of Tim-1 and Tim-3 have not been identified, the
known Tim protein ligands, including Sema4A, are likely to be regulatory
molecules influencing the activation and differentiation of T cells.
Activities
Although recombinant soluble Sema4A does not appear to stimulate B cells
and DCs, Sema4A can provide T cell costimulation
(Kumanogoh et al., 2002a). The
addition of recombinant soluble Sema4A enhances T cell proliferation and IL-2
production following stimulation with anti-CD3 monoclonal antibodies. Soluble
Sema4A promotes the induction of either Th1-cell-mediated IFN-
production or Th2-cell-mediated IL-4 production, depending on the respective
culture conditions. In addition, soluble Sema4A enhances mixed lymphocyte
reactions (MLRs) between allogeneic T cells and DCs. Anti-Sema4A can block the
MLRs, which indicates that Sema4A functions in T cell activation by
influencing stimulatory interactions between T cells and DCs.
The role of Sema4A in immune responses in vivo has been clarified by use of
soluble Sema4A and anti-Sema4A monoclonal antibodies
(Kumanogoh et al., 2002a).
Soluble Sema4A significantly enhances the generation of antigen-specific T
cells. In contrast, administration of anti-Sema4A monoclonal antibodies blocks
antigen-specific T cell priming. Treatment of mice with anti-Sema4A monoclonal
antibodies inhibits the development of EAE induced by myelin oligodendrocyte
glycoprotein (MOG)-peptide administration. Delayed administration of soluble
Sema4A or anti-Sema4A antibodies does not affect the generation of
antigen-specific T cells, which suggests that Sema4A acts early in T cell
activation in vivo (Kumanogoh et al.,
2002a
; Kikutani and Kumanogoh,
2003
).
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Transmembrane forms versus soluble forms |
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How is proteolytic cleavage of the transmembrane form regulated? The
cytoplasmic region of Sema4D appears to be necessary for this regulation. A
serine kinase activity is associated with the cytoplasmic region of human
Sema4D (Elhabazi et al., 1997)
(Fig. 2). Staurosporine (a
cell-permeable, broad specificity inhibitor of serine kinases) enhances the
release of soluble Sema4D (Elhabazi et
al., 2001
), which suggests that serine phosphorylation is involved
in the regulation of Sema4D cleavage. Despite weak cell surface expression,
high levels of soluble Sema4D are detectable in the sera of transgenic mice
expressing a truncated Sema4D lacking the cytoplasmic region
(Watanabe et al., 2001
). Thus,
the cytoplasmic region of Sema4D is necessary for proper regulation of soluble
form generation. Further studies will be required to determine whether these
findings, particularly the regulation of soluble Sema4D production, are
applicable to other transmembrane semaphorins.
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Other semaphorins that play potential roles in the immune system |
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Comeau et al. (Comeau et al.,
1998) have found that both of these viral semaphorins, A39R and
AHVsema, bind to the cellular receptor VESPR/CD232/plexin-C1. A39R-induced
induction of inflammatory cytokines is abrogated by a blocking antibody
against VESPR/CD232/plexin-C1 (Comeau et
al., 1998
). These findings suggest a pathogenic role for viral
semaphorins.
Sema7A
Sema7A (also known as Sema-K1 or CD108) is a molecule homologus to AHVsema.
It was originally discovered as the John-Milton-Hagen human blood group
antigen. Sema7A is a GPI-anchored cell surface glycoprotein preferentially
expressed on activated lymphocytes and thymocytes
(Xu et al., 1998;
Yamada et al., 1999
). Sema7A
specifically binds to VESPR/CD232/plexin-C1
(Tamagnone et al., 1999
),
which confirms that this semaphorin is a cellular counterpart of AHVsema.
Recombinant soluble Sema7A protein exhibits activities against monocytes
similar to those of AHVsema, including induction of the production of
inflammatory cytokines such as TNF-
, IL-6 and IL-8. In addition, Sema7A
demonstrates chemotactic attraction for monocytes
(Holmes et al., 2002
), which
substantiates its role in inflammatory responses. Thus, the viral semaphorins
may have an immunomodulatory effect by mimicking Sema7A. It will therefore be
important to determine the physiological importance of interactions between
Sema7A and VESPR/CD232/plexin-C1.
Class III semaphorin: Sema3A in immune cell migration
Sema3A is the human homologue of collapsin-1, the first identified
vertebrate semaphorin (Kolodkin et al.,
1993). The function of Sema3A as an axonal guidance factor has
been extensively studied in the neurobiology field. Delaire et al. reported
that Sema3A also plays a role in regulating monocyte migration, Sema3A
inhibiting spontaneous monocytic cell migration in a transwell assay
(Delaire et al., 2001
).
Neuropilin-1, the known receptor of Sema3A, is not expressed on the target
immune cells, however, which suggests that the inhibitory effect of Sema3A on
immune-cell migration is mediated by receptors different from those previously
known to bind within the nervous system
(Delaire et al., 2001
).
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Why is the receptor system so complicated? |
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The semaphorin receptor system is more complex than previously thought.
Several novel components besides plexins and neuropilins are emerging, aiding
our understanding of the complexity of the system. Off-track, a protein
similar to receptor tyrosine kinases that contains a catalytically inactive
kinase domain, associates with Drosophila melanogaster PlexinA to
mediate Sema1a repulsive functions
(Winberg et al., 2001). L1, a
cell adhesion molecule in the immunoglobulin superfamily, plays a role in
repulsive responses to the class III semaphorin Sema3A as part of a
neuropilin-plexin receptor complex
(Castellani et al., 2002
).
Moreover, as mentioned above, plexin-B1 forms a receptor complex with Met,
whose intrinsic kinase activity is required for promoting epithelial cell
invasive growth in response to Sema4D
(Giordano et al., 2002
). These
recent findings suggest that many semaphorin receptors exist as large
holoreceptor complexes that mediate ligand binding and signal transduction.
The pairing of receptor components can also have diverse biological functions
in a broad range of tissues. It will be crucial to carefully re-evaluate the
composition of several semaphorin receptors formerly thought to contain one or
a few different proteins, including CD72 and Tim-2. More comprehensive studies
on receptor usage, including the presence or absence of additional receptor
components in both lymphoid and non-lymphoid tissues, will help delineate the
pleiotropic effects of the multiple semaphorin-receptor systems.
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Are semaphorin interactions clinically relevant? |
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In contrast, inhibition of immune semaphorins may prove to be a therapeutic
approach for the control of certain immune disorders. Sema4D-deficient mice
are resistant to EAE induced following administration of MOG-derived peptides,
owing to the impaired generation of MOG-reactive T cells
(Kumanogoh et al., 2002b).
Sema4A blockade also suppresses the development of EAE
(Kumanogoh et al., 2002a
),
which suggests that these molecules serve as potential targets in the
treatment of autoimmunity. In addition, an antibody against
VESPR/CD232/plexin-C1 inhibits viral semaphorin-induced induction of
inflammatory cytokines by monocytes (Comeau
et al., 1998
). Delaire and colleagues recently reported that
soluble Sema3A and Sema4D inhibits both spontaneous and MCP-3-induced
monocytic cell migration (Delaire et al.,
2001
). They might thus prove to be useful clinical
anti-inflammatory agents. The manipulation of immune semaphorin function,
through either reinforcement or inhibition by recombinant proteins and
specific antibodies or drugs, is a crucial area for future clinical
studies.
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Further questions |
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Semaphorins other than Sema4D and Sema4A also appear to function in immunity, representing a new family of immunoregulatory molecules. Because the studies with the 'immune semaphorins' suggest that these molecules function in autoimmune diseases and viral infections, other semaphorins may prove to be viable targets for research into therapies for immune disorders and infectious diseases. Future studies clarifying the biological functions of semaphorins in the immune system should help establish a new paradigm of cell-cell communication through semaphorin networks.
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Acknowledgments |
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