DNAM-1 (CD226): A Two-Sword Fencer for ... - Bentham Science

Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, 4, 53-58 53
DNAM-1 (CD226): A Two-Sword Fencer for Innate and Adaptive
Immunity
Akira Shibuya*, Satoko Tahara-Hanaoka and Kazuko Shibuya
Department of Immunology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences,
and Center for TARA, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8577, Japan
Abstract: The leukocyte adhesion molecule DNAM-1 (CD226) is a member of the immunoglobulin superfamily and
constitutively expressed on the majority of CD4 + and CD8 + T lymphocytes, natural killer (NK) cells,
monocytes/macrophages, platelets and megakaryocytes and a subset of B lymphocytes. The poliovirus receptor (CD155)
and its family member nectin 2 (CD112) have recently been identified as the ligands for DNAM-1. Interaction of DNAM-
1 with the ligands induces NK cell- and CD8 + T cell-mediated cytotoxicity and cytokine secretion. Upon antigen
recognition by the T cell receptor, DNAM-1 physically associates with the αLβ2 integrin adhesion molecule LFA-1 and
plays an essential role for LFA-1-mediated costimulatory signals for differentiation from naïve CD4 + T cells toward Th1
cells. Moreover, DNAM-1 is involved in macrophage and platelet activation and adhesion to vascular endothelial cells.
Thus, DNAM-1 is involved in a variety of hematopoietic cell functions for innate and adaptive immunities.
INTRODUCTION
Intercellular adhesion molecules play important roles in
lymphocyte-mediated immune responses (reviewed in [1,
2]). Leukocyte adhesion molecules not only mediate
intercellular binding but also transduce signals in immune
cells. They are often expressed on multi-lineages of
hematopoietic cells, rather than on a single cell type, and are
involved in a variety of cellular functions. The leukocyte
adhesion molecule DNAM-1 (CD226) is a ~65 kDa
glycoprotein expressed on cell surface of T cells, NK cells,
monocytes/macrophages, platelets and megakaryocytes and a
subset of B cells [3]. It is a member of the immunoglobulin
(Ig)-superfamily containing 2 Ig-like domains of the V-set
(Fig. 1) and encoded by a gene on chromosome 18q22.3 [3].
Here, we review its molecular and functional characteristics
in innate and adaptive immunities.
IDENTIFICATION OF A NOVEL ADHESION MOLE-
CULE DNAM-1
DNAM-1 was first identified by protein purification by
using the anti-DNAM-1 mAb DX11 [3]. DX11 was
generated by immunizing mice with human NK cells and
selected because of its abilities to block cytotoxicity against
a variety of tumor cell lines and also to induce antibodymediated
re-direct cytolysis against the murine Fc receptorbearing
P815 mastocytoma (Fig. 2). In peripheral blood,
DNAM-1 is expressed on the majority of α/β - TcR + T cells,
~
γ/δTcR + T cells, NK cells (CD3 - , CD56 + ), monocytes
(CD14 + ), and a subset of B cells, but is not on granulocytes
*Address correspondence to this author at the Department of Immunology,
Institute of Basic Medical Sciences, Graduate School of Comprehensive
Human Sciences, University of Tsukuba, 1-1-1, Ten-nodai, Tsukuba,
Ibaraki 305-8577, Japan; Tel: 81-29-853-3474; Fax: 81-29-853-3410,
E-mail: ashibuya@md.tsukuba.ac.jp
Fig. (1). Interaction of LFA-1 and DNAM-1 with their
respective ligands
DNAM-1 (CD226) is a ~65 kDa glycoprotein expressed on cell
surface of T cells, NK cells, monocytes/macrophages, platelets and
megakaryocytes and a subset of B cells and a member of the
immunoglobulin (Ig)-superfamily containing 2 Ig-like domains of
the V-set. The ligands for DNAM-1 are the poliovirus receptor
(CD155) and its family member nectin-2 (CD112), which are
broadly expressed on epithelial, endothelial and neuronal cells.
DNAM-1 is physically associated with LFA-1 in NK cells and
activated T cells, and involved in LFA-1-mediated signaling.
nor erythrocytes. DNAM-1 is also expressed on a subset of
thymocytes co-expressing high surface density CD3 and on a
variety of transformed hematopoietic cells [3].
1568-0142/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.

54 Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 1 Shibuya et al.
Fig. (2). Screening of mAbs recognizing signal transducing molecules involved in NK cell function
Monoclonal antibodies specific for signal transducing activating receptor expressed on NK cells are able to be selected by the screening
procedures; 1) an anti-activating receptor mAb can induce antibody-mediated re-directed cytolysis against the murine Fc receptor-bearing
P815 mastocytoma that is originally a human NK-resistant target (signaling induction), 2) on the other hand, the anti-activating receptor mAb
can also inhibit NK cell-mediated cytotoxicity against NK-sensitive tumor cell targets that express a ligand for the activating receptor
(signaling block).
The DNAM-1 gene is located on chromosome 18q22.3
[3] . The molecular weight of DNAM-1 was ~65 KD when
analyzed by SDS-PAGE under both reducing and nonreducing
conditions. The mobility of DNAM-1 decreased
from ~65 KD to ~35 KD after treatment with N-glycosidase
F, consistent with the size of the polypeptide predicted from
the DNAM-1 cDNA and the presence of 8 potential N-linked
glycosylation sites in the extracellular domain [3].
IDENTIFICATION OF THE LIGANDS FOR DNAM-1
The DNAM-1 ligands have recently been identified by
the two groups independently. Moretta and colleagues have
generated a mAb that blocks NK cell-mediated cytotoxicity
against certain tumors and purified a protein expressed on a
tumor target recognized by the mAb [4]. Our group
generated the fusion protein of extracellular portion of
DNAM-1 with human IgG Fc portion (DNAM-1-Fc) and
performed an expression cloning with a retroviral cDNA
library prepared from a human osteosarcoma cell line, using
DNAM-1-Fc as a probe [5]. Both groups have independently
identified the human poliovirus receptor (PVR) α (CD155)
and its isoform PVRδ as the ligands for DNAM-1 (Fig. 1).
CD155 is a member of the poliovirus receptor-related (PRR)
family, which consists of CD111 (nectin-1/PRR-1), CD112
(nectin-2/PRR-2), nectin-3 (PRR-3) and nectin-4 (PRR-4), in
addition to CD155 [6-11]. The ectodomains of the PRR
family molecules are composed of three Ig-like domains that
share 30 to 55% amino acid identity [11]. Out of these
family members, CD112 was also found to be another ligand
for DNAM-1 [4, 5]. PRR-1, PRR-2, PRR-3 and PRR-4
mediate homophilic interactions as well as heterophilic
interactions [9-12], as demonstrated in Fig. 3. Interestingly,
activated T cells and NK cells express CD96 (also called
Tactile) [13], which only shows ~20% homology with
DNAM-1, has been shown to also recognize CD155 and
promote NK cell adhesion and activation [14].
Although the binding affinities between DNAM-1-Fc and
CD155-Fc or CD112-Fc are comparable (Kd=2.3 x 10 -7 M
and 3.1 x 10 -7 M, respectively), BW5147 transfectant
expressing CD112 bound to DNAM-1-Fc less than that
expressing CD155 [5]. This may be caused by the
homophilic interaction of CD112 [15, 16]. In fact, DNAM-1-
Fc binding to the CD112 transfectant was augmented
substantially after pretreatment of the transfectant with a
mAb that blocks homophilic interaction of CD112 [5],
suggesting that DNAM-1 binding to CD112 on cell surface
may be impaired by homophilic interaction of CD112.
DNAM-1-Fc binding to CD155 is blocked by an
antibody that recognizes an epitope on the first Ig-like
domain of CD155 (our unpublished observation), suggesting
that DNAM-1 may bind to a site of the first Ig-like domain
of CD155, which is also the entry site of poliovirus [17-19].
CD112 is a receptor for alphahelpes virus [20]. It should be
an interesting issue whether or not DNAM-1 binding to
CD155 or CD112 effects the poliovirus or alphahelpes virus
infections.
DNAM-1 IS INVOLVED IN NK CELL- AND
ANTIGEN-SPECIFIC T CELL-MEDIATED CYTO-
TOXICITIES
Anti-DNAM-1 mAb effectively blocks NK cell-mediated
cytolysis of a variety of tumor targets, including colon
cancer cell line, Colo-205, but not EB virus-transformed B
cell line Jy or 721.221. These results are in agreement with
the observations that, while Colo-205 expresses both CD155
and CD112, EB virus-transformed B cell lines including both
Jy and 721,221 do neither CD155 nor CD112 (Fig. 4).

DNAM-1 (CD226): Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 1 55
Fig. (3). Interaction between poliovirus receptor (PVR) family, DNAM-1 and Tactile
DNAM-1 binds to both poliovirus receptor (PVR; CD155) and nectin-2 (CD112). Nectin-2 can also bind to both nectin-3 and nectin-2 itself
(homophilic binding). PVR (CD155) can also bind to both nectin-3 and Tactile (CD96) that is expressed on activated T cells and NK cells
and shows ~20% homology with DNAM-1. Nectin-4, Nectin-1 and Nectin-3 also mediate homophilic binding as well as heterophilic
interaction, as shown in this figure.
Ectopic expression of CD155 and/or CD112 rendered mouse
BW5147 T cells more susceptible to NK cell-mediated
cytotoxicity, and killing was specifically inhibited by anti-
DNAM-1 mAb [5], demonstrating functional interactions of
DNAM-1 with CD155 and CD112 that induce cytolytic
activity in NK cells.
Both Colo-205 and Jy express HLA-A2 and these tumor
cell lines are sensitive targets by HLA-A2-specific CTL [3].
Anti-DNAM-1 mAb blocks cytotoxicity of Colo-205, but not
Jy, mediated by HLA-A2-specific CTL (Fig. 4). These
results indicate that DNAM-1 mediates activation signals for
cytotoxicity by antigen-specific CTL, as well as NK cells.
DNAM-1 AND LFA-1 COOPERATE IN
CYTOTOXICITY AND CYTOKINE SECRETION
MEDIATED BY NK CELLS
As described above, anti-DNAM-1 mAb mediates redirect
cytolysis against the murine Fc receptor-bearing P815
mastocytoma by NK cells. However, this function was
defective in NK cell clones from patients with leukocyte
adhesion deficiency, whose leukocytes do not express the β2
integrin adhesion molecules (i.e., CD11a/CD18 (LFA-1),
CD11b/CD18 (Mac-1), CD11c/CD18) [21-23]. However,
genetic reconstitution of cell surface expression of LFA-1
restored the ability of DNAM-1 to initiate anti-DNAM-1
mAb induced cytotoxicity [24], indicating a functional
relationship between DNAM-1 and LFA-1. Further studies
demonstrated that CD11a was co-immunoprecipitated with
DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells
[24]. These results indicate the physical association of LFA-
1 with DNAM-1 in NK cells and activated T cells. Anti-
LFA-1 (CD18) mAb inhibit the NK cell-mediated
cytotoxicity against the BW5147 transfectants expressing
CD155, CD112 or both [5]. These results suggest that LFA-1
and DNAM-1 cooperate in triggering cytotoxicity mediated
by NK cells. Moreover, while interferon-γ secretion was
scarcely detected when LFA-1 and DNAM-1 were
stimulated independently with their ligands ICAM-Fc or
CD155-Fc, it was dramatically augmented after simultaneous
stimulation of both LFA-1 and DNAM-1[5], indicating the
cooperation of LFA-1 and DNAM-1 also in cytokine
secretion from NK cells.
DNAM-1 IS INVOLVED IN LFA-1-MEDIATED
COSTIMULATORY SIGNALS FOR TRIGGERING
CD4+ NAÏVE T CELL DIFFERENTIATION AND
PROLIFERATION
Studies using mice with disrupted CD11a or CD18 genes
have indicated a requirement for LFA-1 in T cell
proliferation induced by the TCR/CD3 complex [25, 26].
Moreover, recent reports have suggested that LFA-1 may be
involved in IL-12-independent helper T cell differentiation
toward Th1 [27, 28]. These observations indicate that LFA-1
not only mediates intercellular binding but also may deliver
costimulatory signals in T lymphocytes [29]. Upon antigen
recognition or CD3 mAb stimulation, LFA-1 physically
associates with DNAM-1 in CD4 + helper T cells [24]. Coligation
of both CD3 and CD18 with mAbs induced DNAM-
1 tyrosine phosphorylation at residue 322 of DNAM-1 in
naïve CD4 + T cells, suggesting that the tyrosine
phosphorylation at residue 322 of DNAM-1 may be
important for LFA-1-mediated signaling in T cells.
Transduction of mutant (Y-F 322 ) DNAM-1 by lentiviral
vector into naïve CD4 + helper T cells inhibited Th1
development initiated by CD3 and LFA-1 ligations [30].
Moreover, proliferation induced by LFA-1 costimulatory
signal was suppressed in mutant (Y-F 322 ) DNAM-1-
transduced naïve CD4 + and CD8 + T cells in the absence of
IL-2 [30]. These results suggest that DNAM-1 is involved in

56 Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 1 Shibuya et al.
Fig. (4). DNAM-1 is involved in cytotoxicity against Colo-205, but not Jy, by antigen-specific CTL
HLA-A2-specific CTL lyses HLA-A2-bearing tumor Colo-205 and Jy. Anti-DNAM-1 mAb can inhibit cytotoxicity against Colo-205, but
not Jy (A), because Colo-205 expresses the DNAM-1ligands CD155 and CD112, but Jy does not express any of these ligands (B).
LFA-1-mediated costimulatory signals for triggering naïve T
cell differentiation and proliferation.
ROLE OF DNAM-1 IN MACROPHAGE MIGRATION
AND INFILTRATION
The DNAM-1 ligands are expressed on a variety of cells,
including neuronal, epithelial, endothelial and fibroblastic
cells [31]. They are involved in the formation of both
adherence and tight junctions in epithelial cells [32]. Lopez
and colleagues have recently demonstrated that DNAM-1-Fc
bind to cell junctions on primary vascular endothelial cells,
and anti-CD155 mAb, but not anti-CD112 mAb, abrogated
this binding [33]. They demonstrated, moreover, that anti-
DNAM-1 and anti-CD155 mAbs inhibited transmigration of
macrophages through endothelium. These results indicate
that DNAM-1 regulates macrophage extravasation via its
interaction with CD155 expressed on endothelial junctions.
SIGNAL TRANSDUCTION MEDIATED BY DNAM-1
Unlike β2 integrin adhesion molecules, adhesion of
DNAM-1 to its ligands does not require divalent cations
[34]. However, the serine phosphorylation at residue 329 in
the cytoplasmic portion of DNAM-1 by PKC activation
plays an important role for ligand binding of DNAM-1[34].
In addition, the serine phosphorylation is also required for
physical association of DNAM-1 with LFA-1 in T cells [24].
DNAM-1 as well as LFA-1, PKC and the protein tyrosine
kinase Fyn are recruited in lipid rafts upon stimulation of the
TCR, resulting in the formation of the immunological
synapse (IS) at the interface with antigen presenting cells
(APC) [30]. However, the site-specific mutant DNAM-1 at
the serine residue 329 is not able to associate with lipid rafts
(Shirakawa, et al.; unpublished observation). A recent report
has demonstrated that T cell stimulation with phorbol ester
or DNAM-1 cross-linking induces DNAM-1 and actinbinding
protein 4.1G to associate tightly with the
cytoskeleton, and the DNAM-1 from such activated cells
now can bind to the amino-terminal region of 4.1G [35].
Together, these results suggest a possibility that the serine
phosphorylations of DNAM-1 may be involved in interaction
between DNAM-1 and 4.1G.
DNAM-1 IS INVOLVED IN ACTIVATION AND
ADHESION OF PLATELETS
Burns and colleagues previously described a novel
membrane glycoprotein, designated platelet and T cell
activation antigen-1 (PTA1), which is involved in platelet
activation and aggregation [36]. Molecular cloning of PTA-1
revealed that it was identical to DNAM-1 [37]. While crosslinking
DNAM-1 with anti-DNAM-1 mAb induces platelet
activation and aggregation [36, 38], F(ab’)2 fragments of

DNAM-1 (CD226): Curr. Med. Chem. – Anti-Inflammatory & Anti-Allergy Agents, 2005, Vol. 4, No. 1 57
Fig. (5). DNAM-1 is involved in adhesion, infiltration and signaling in a variety of hematopoietic cells
Interaction of DNAM-1 with DNAM-1 ligands induces cytotoxicity and cytokine secretion mediated by NK cells and T cells (1). In addition,
DNAM-1 mediates intercellular adhesion between monocytes/macrophages, platelets and megakaryocytes and endothelial cells (2). DNAM-
1 is also involved in LFA-1-mediated co-stimulatory signals for Th1 differentiation from naïve CD4 + helper T cells and for naïve T cell
proliferation (3).
anti-DNAM-1 mAb failed to induce platelet activation (our
unpublished observations). However, stimulation of FcγR
alone does not activate platelets, suggesting that DNAM-1
and FcγR might cooperate in platelet activation. DNAM-1-
Fc bound to human umbilical vascular endothelial cells
(HUVEC), indicating that HUVEC express the ligands for
DNAM-1 [39]. In fact, mAbs against CD155 and CD112
specifically stained HUVEC [5]. Thrombin-activated, but not
resting, platelets bind to intact HUVEC, and anti-DNAM-1
mAb specifically inhibited the binding, indicating that
DNAM-1 mediates the intercellular binding between
thrombin-activated platelets and HUVEC [39]. DNAM-1 is
also expressed on primary megakaryocytes and
megakaryocytic cell lines. Anti-DNAM-1 mAb inhibit
binding of megakaryocytic cell lines to HUVEC [39],
suggesting that DNAM-1 may be involved in megakaryocyte
adhesion to vascular endothelial cells.
CONCLUDING REMARKS
In summary, DNAM-1 is expressed on a variety of
hematopoietic cells. Interaction of DNAM-1 with DNAM-1
ligands CD155 and CD112 induces intercellular adhesion,
infiltration and cell signaling (Fig. 5), resulting in a variety
of cellular responses including innate and adaptive
immunities. Recently, gibbon, monkey and mouse
homologues of DNAM-1 have been identified ([40] and our
unpublished data). In vivo analysis of DNAM-1 function
using these animal models should further elucidate its
cellular roles in innate and adaptive immunities.
ACKNOWLEDGEMENT
We thank Lewis Lanier, Joe Phillips and the members of
our laboratory for discussion and Yurica Soeda for
secretarial assistance. This work was supported in part by the
grants provided by the Ministry of Education, Science and
Culture of Japan (to A.S., S.T-H., and K.S.), Special
Coordination Funds of the Science and Technology Agency
of the Japanese Government (to A.S.), the Uehara Memorial
Foundation (to A.S.), the Yasuda Memorial Foundation (to
A.S.), and the Novartis foundation (to A.S.).
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Received: August 02, 2004 Accepted: August 19, 2004