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Natural killer cell receptor signaling
Lewis L Lanier
Natural killer (NK) cell immune responses are regulated by a
balance of activating and inhibitory signals transmitted by cell
surface receptors. Immunoreceptor tyrosine-based inhibition
motifs in the cytoplasmic domains of inhibitory NK receptors
recruit tyrosine or lipid phosphatases, which modulate the
activation signals transmitted by receptors linked to the Syk and
ZAP70 tyrosine kinases and phosphatidylinositol-3 kinases. In
addition, recent studies of gene-deficient animals, in particular
Syk and ZAP70 double-deficient mice, suggest that NK cells
possess a robust and potentially redundant receptor system to
ensure their development and function.
Addresses
University of California at San Francisco, Department of Microbiology
and Immunology and the Cancer Research Institute, 513 Parnassus
Avenue, Box 0414, San Francisco, CA 94143-0414 USA
e-mail: [email protected]
Current Opinion in Immunology 2003, 15:308–314
This review comes from a themed issue on
Lymphocyte activation
Edited by Andrey Shaw and André Veillette
0952-7915/03/$ – see front matter
ß 2003 Elsevier Science Ltd. All rights reserved.
DOI 10.1016/S0952-7915(03)00039-6
Abbreviations
ERK
extracellular signal-regulated kinase
GM-CSF
granulocyte macrophage colony-stimulating factor
IFN
interferon
ITAM
immunoreceptor tyrosine-based activation motif
ITIM
immunoreceptor tyrosine-based inhibition motif
KIR
killer cell immunoglobulin-like receptor
LAT
linker for the activation of T cells
NK cell
natural killer cell
PI3 kinase phosphatidylinositol-3 kinase
PLC
phospholipase C
SAP
SLAM-associated protein
SH
Src homology
SHIP
SH2 domain-containing inositol-5 phosphatase
SHP
SH-containing tyrosine phosphatase
SLAM
signaling lymphocyte activation molecule
TCR
T-cell antigen receptor
Introduction
The observation that natural killer (NK) cells preferentially kill certain cells if they lack the expression of MHC
class I predicted the existence of inhibitory receptors
that regulate NK cell activation. Activation of NK cells in
the absence of MHC class I on the target cell was
considered to occur by ‘default’, resulting in the killing
of any cell lacking MHC class I. However, this notion
failed to consider the fact that NK cells do not kill
Current Opinion in Immunology 2003, 15:308–314
erythrocytes, which in humans do not express MHC
class I, and they rarely kill normal resting cells even if
they express only low levels of MHC class I. Furthermore, the ‘killing by default’ concept couldn’t explain
how an NK cell could attack something that it couldn’t
recognize in a positive fashion. The recent discovery of a
plethora of activating NK receptors helps to resolve the
question of how NK cells recognize potential targets. In
addition, it has become apparent that the engagement of
inhibitory receptors for MHC class I does not globally
suppress NK cell activation, but rather a balance
between stimulation and inhibition dictates the nature
of the immune response.
NK receptors and signaling pathways
NK receptors associated with ITAM-bearing
transmembrane adaptor proteins
Perhaps not surprisingly, the positive and negative signaling pathways used by NK cells share many common
features with the immune receptors expressed on B and
T lymphocytes. Although numerous NK cell receptors
have been identified, these converge on a few biochemical
pathways employed by most leukocytes (reviewed in
[1–4]). In particular, the activating NK cell receptors
that are best characterized use signaling elements also
employed by the B- and T-cell antigen receptors; there
is a division of labor, with ligand recognition and signal
transduction delegated to independent protein subunits
and assembled into the functional receptor complex.
Signals are transmitted by small transmembraneanchored adaptor proteins that possess immunoreceptor
tyrosine-based activation motifs (ITAMs) in their cytoplasmic domains. NK cells express the ITAM-bearing
CD3z, FceRIg and DAP12 adaptor proteins. CD3z and
FceRIg can be expressed as disulfide-bonded homodimers or disulfide-bonded heterodimers, whereas DAP12
is exclusively expressed as a disulfide-bonded homodimer. Associations between these ITAM adapters and
their receptors are predominantly mediated by interactions within their transmembrane regions, often involving
pairs of oppositely charged amino acids that form stable
salt bridges. Numerous NK receptors have been identified that pair with DAP12 (e.g. in mice several activating
Ly49 receptors, CD94/NKG2C and CD94/NKG2E, and
in humans several activating killer cell immunoglobulinlike receptors [KIRs], CD94/NKG2C and NKp44;
Figure 1), CD3z or FceRIg (e.g. NKR–P1C and CD16
in mice, and NKp30, NKp46 and CD16 in humans;
Figure 2). Interestingly, in mice CD16 is unable to pair
with CD3z, but uses FceRIg. A recent study by Arase et al.
[5] reported that heterodimers of CD3z and FceRIg
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NK receptor signaling Lanier 309
Figure 1
Murine
CD16
Human
NKp46
Murine
NKR–P1C
D
R
Human
CD16
Human
NKp30
D
K
K
R
D
D
D
D
D
D
ITAM
FcεRIγ–FceRIγ
FcεRIγ–CD3ζ
CD3ζ–CD3ζ
Syk, ZAP70
Current Opinion in Immunology
NK cell receptors associated with the FceRIg and CD3z adaptor proteins. Human CD16, NKp30 and NKp46 can associate with homodimers or
heterodimers of the FceRIg and CD3z adapter proteins. In contrast, mouse NKR–P1C and mouse CD16 associate with homodimers of mouse FceRIg,
but not CD3z. Unlike other receptors that associate with FceRIg and CD3z, CD16 has an acidic residue, instead of a basic amino acid in its
transmembrane, as shown using amino acid one-letter code. The pink domains represent ITAMs.
compete with FceRIg homodimers and negatively regulate CD16-mediated activation of NK cells.
Ligation of any ITAM-bearing receptor complexes
results in the recruitment and activation of the tyrosine
kinases Syk and ZAP70, both of which are expressed by
all NK cells. The most extensively studied NK receptor is
CD16, a low-affinity IgG receptor responsible for antibody-dependent cellular cytotoxicity (ADCC). CD16
signaling in NK cells, initiated by either CD3z or FceRIg
is quite similar to TCR-induced signal transduction in T
cells; phosphorylation of the ITAMs is probably mediated
by a src family kinase, thereby facilitating recruitment
of Syk and ZAP70. Downstream events include the
phosphorylation of SLP-76, 3BP2 [6], Shc, [7] p85 PI3kinase, c-Cbl, phospholipase C (PLC)-g1 and PLC-g2,
the mobilization of Grb2, linker for the activation of
T cells (LAT), Vav-1 and Vav-2, the elevation of intracellular Ca2þ levels, and the activation of Rho, Ras, p38
mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK).
Signaling via CD16 activates nuclear factor of activated T
cells (NFAT) and results in the production of cytokines,
Figure 2
KIR2DS
Ly49D, Ly49H
NKp44
R
R D
D
DAP12–DAP12
K D
D
DAP12–DAP12
K D
D
DAP12–DAP12
Current Opinion in Immunology
NK cell receptors associated with DAP12. Mouse Ly49D and Ly49H, human KIR2DS (and probably KIR3DS), and human NKp44 receptors associate
with homodimers of DAP12.
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Current Opinion in Immunology 2003, 15:308–314
310 Lymphocyte activation
including IFN-g, GM-CSF and several chemokines, and
causes degranulation of NK cells. Similar to TCR signaling, CD16 activation can cause apoptosis in IL-2-activated NK cells. The biochemical events accompanying
stimulation of other ITAM-based NK receptors are not
well characterized, but will probably be similar to CD16induced activation. As with CD3z or FceRIg, stimulation
of NK cells through DAP12 activates Syk, and ZAP70 and
initiates NK cell-mediated cytotoxicity and cytokine
production. Ortaldo and colleagues [8] used microarray
analysis to explore gene transcription induced by activation through the Ly49D–DAP12 receptor complex in
murine NK cells, revealing genes that are either increased
or decreased in expression. Of interest, the most potently
induced genes were certain chemokines, such as macrophage-inflammatory protein-1a or –1b (MIP-1a, MIP-1b),
that might be involved in recruitment of other leukocytes
to sites of infection.
The activating NKG2D receptor complex
The NKG2D receptor has received considerable attention as it allows NK cells to recognize virus-infected and
transformed cells that have upregulated expression of the
NKG2D ligands (RAE-1 and H-60 in mice, and MICA,
MICB and ULBP in humans; reviewed in [1–3]).
Expression of NKG2D on the cell surface requires its
association with DAP10, a transmembrane-anchored
adaptor protein expressed as a disulfide-linked homodimer. The short cytoplasmic domain of DAP10 contains a
YxxM motif (in amino acid one-letter code, where x
denotes any amino acid) that binds to the p85 subunit
of phosphatidylinositol-3 kinase (PI3 kinase) and Grb2
upon phosphorylation. Although the ‘long’ NKG2D
(NKG2D-L) glycoprotein associates exclusively with
DAP10, recent studies by Diefenbach and colleagues
[9] have identified a ‘short’ (NKG2D-S) alternatively
spliced isoform of mouse NKG2D that is able to associate
with both DAP10 and DAP12 (Figure 3). NKG2D-S was
also observed in NK cells obtained from DAP10-deficient
mice [10]. Resting NK cells express only NKG2D-L;
however, after activation by IL-2 in vitro or by poly-I:C
(an inducer of type I interferons) in vivo, NK cells also
transcribe NKG2D-S [9]. Therefore, in activated NK
cells the NKG2D receptor stimulates both ITAM-based
and PI3 kinase-associated pathways, providing stimulation and co-stimulation by the same receptor.
NKG2D is also expressed in activated mouse CD8þ T
cells, which also express DAP10 but not usually DAP12
[11]. Consequently, in T cells, NKG2D is unable to
stimulate ZAP70 or Syk and can only provide co-stimulation for TCR-induced T-cell activation. The downstream
events accompanying NKG2D stimulation have not been
extensively characterized, but may be complicated to
dissect if DAP10, DAP12 and potentially other molecules
are involved, depending on the particular cell type and
their activation state. Interestingly, Sutherland et al. [12]
observed that stimulation of human NK cells with soluble
NKG2D ligands resulted in the activation of Janus kinase
2, STAT5, ERK, MAPK and PI3 kinase/Akt signal transduction pathways. Although activation of PI3 kinase/Akt
is explained by the presence of the YxxM motif in
DAP10, the mechanism by which the other signaling
pathways are recruited requires further investigation. In
our own studies of NKG2D signaling in human NK cells,
we have observed activation of PI3 kinase and Akt, but
not phosphorylation of Syk, ZAP70 or ERK (A Zingoni,
L Lanier, unpublished data). However, as noted above,
NKG2D may be hardwired to different activation pathways in different cells.
The paradigm of stimulation of T cells through a dominant TCR and co-stimulation through secondary receptors that amplify the TCR signal may not apply to NK
Figure 3
NKG2D-S
NKG2D-S
DAP12–DAP12
R
R D
D
ITAM
Syk, ZAP70
R
NKG2D-L
DAP10–DAP10
DAP10–DAP10
R D
D
R
R D
D
YINM
YINM
p85 PI3 kinase
Current Opinion in Immunology
Association of distinct NKG2D isoforms with DAP12 and DAP10. A ‘short’ isoform of mouse NKG2D (NKG2D-S) containing a truncated cytoplasmic
domain on the amino terminus associates with both DAP12 (leading to signaling through Syk or ZAP70 by association with ITAMs) and DAP10
homodimers. The ‘long’ NKG2D isoform (NKG2D-L) associates only with DAP10 homodimers. As yet, in humans only the NKG2D-L isoform has been
identified. YINM is single-letter amino acid code.
Current Opinion in Immunology 2003, 15:308–314
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NK receptor signaling Lanier 311
cells. There is no evidence for a dominant stimulatory
receptor in NK cells, rather activation might be achieved
by the summation or synergy of multiple receptors.
NK receptor signaling not involving ITAM-based or
DAP10 pathways
NK receptors not using ITAM adapters or DAP10 have
also been defined. The CD244 (2B4) and NTB-A [13]
receptors contain TxYxxV/I motifs in their cytoplasmic
domains, which permit association with the cytoplasmic
SLAM-associated protein (SAP) adaptor protein (also
called SH2 domain-containing protein 1A; SH2D1A;
reviewed in [14]). Upon activation, CD244 associates
with LAT and localizes to lipid rafts, a critical interaction
for CD244-mediated signal transduction [15,16]. SAP is of
interest because a loss-of-function SAP gene mutation in
human X-linked lymphoproliferation disease results in
life-threatening infections with Epstein-Barr virus (EBV)
and EBV-associated B-cell malignancies. SAP and its
associated receptors is reviewed in greater depth in
another article in this section [17].
CD160 is an activating NK receptor that recognizes certain
HLA class I molecules. Similar to other glycosylphosphatidylinositol (GPI)-anchored proteins, CD160 probably
resides in lipid rafts and might thus associate with kinases
localized in these domains to achieve signaling [18].
Although not restricted to NK cells, integrins (in particular, lymphocyte function-associated antigen [LFA]-1;
also called CD11a/CD18) have been implicated in NK
cell activation and effector function. In a recent study by
Barber and Long [19], human NK cells adhere to insect
cells transfected with human intercellular adhesion molecule 1 (ICAM-1, CD54) and this is greatly enhanced in
the presence of IL-2 or IL-15. In addition, if the insect
cells co-express CD58 or CD48, (ligands for the CD2
and CD244 [2B4] receptors, respectively) adhesion is
enhanced. Inhibitors of src kinases or PI3 kinase prevented
LFA-1-mediated, actin-dependent adhesion. These studies extend previous findings implicating LFA-1 signaling in NK cell adhesion, degranulation and cytokine
production.
Inhibitory NK receptor signaling
Paradoxically, the mechanism of the inhibitory NK cell
receptors was resolved long before an understanding of the
activation receptors became apparent (extensively
reviewed in [20]). All of the inhibitory KIRs and Ly49
receptors possess immunoreceptor tyrosine-based inhibition motifs (ITIMs) in their cytoplasmic domains. Upon
engaging a MHC class I ligand, these ITIMs are phosphorylated and recruit phosphatases to counteract cellular
activation. The predominant phosphatases associated with
KIR and Ly49 are Src homology (SH)-containing tyrosine
phosphatase (SHP)-1 and SHP-2. However, Wang et al.
[21] have recently shown an association of inhibitory Ly49
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receptors with the lipid phosphatase SH2 domain-containing inositol-5 phosphatase (SHIP). The substrates of these
phosphatases are still under active investigation, but they
might depend upon which activating receptors are being
modulated. A critical central substrate of SHP-1 may be
Vav, as revealed by substrate-trapping experiments using
a catalytically inactive KIR–SHP-1 chimeric receptor
(EO Long, personal communication).
One of the human KIR molecules, KIR2DL4 (CD158d) is
schizophrenic, containing an ITIM in the cytoplasmic
domain but also exhibiting activating functions [22,23,
24]. When introduced into a chimeric receptor, the
KIR2DL4 cytoplasmic domain inhibits NK cell activation.
By contrast, cross-linking the endogenous KIR2DL4 on
NK cells can activate cell-mediated cytotoxicity and cytokine production. A positively charged amino acid in the
transmembrane of KIR2DL4 suggests association with an
adaptor protein, but this receptor apparently does not pair
with any of the usual suspects (DAP12, DAP10, CD3z or
FceRIg). The physiological function and ligand of this
receptor, when identified, should prove interesting.
Spatial organization of NK receptors on
the membrane
Now that many of the NK receptors have been identified,
attention has turned to their spatial localization in the
membrane and their movement upon encountering target
cells expressing relevant ligands. Several laboratories
have investigated the localization of receptors and signaling molecules during encounters between NK cells and
target cells [25–29]. There is a consensus that NK cellmediated cytotoxicity requires adhesion to target cells,
polarization of the relevant receptors and exocytosis of
perforin-containing granules at the interface.
When an appropriate HLA class I ligand for an inhibitory
NK receptor is present on the target cells, the inhibitory
receptors are redistributed to the interface between NK
cells ant target cells and killing may be diminished. Vyas
and colleagues [27,28] reported that when human NK
cells encounter NK-sensitive targets there is a localization
of Lck, protein kinase Cy, PLC-g1, Itk, Syk, ZAP70 and
SLP-76 to the intercellular interface, together with the
polarization of talin (the microtubule organizing center)
and lysozymes. SHP-1 was also found to localize to the
cellular interface; however, in the presence of a ligand for
an inhibitory KIR on the target cell, SHP-1 entered the
central zone of the interface but was only seen at the
periphery of the region upon encounters with NK-sensitive targets [27,28]. Previous studies demonstrated that
chemical inhibitors of the src and Syk family kinases
prevented target cell-induced lipid raft formation in
NK cells and expression of a dominant-negative SHP-1
prevented the activity of an inhibitory KIR in disruption
of lipid rafts at the NK cell and target interface. The
generation of functional lipid rafts at the interface of NK
Current Opinion in Immunology 2003, 15:308–314
312 Lymphocyte activation
cells and target cells required an intact RhoA-ROCKLIMK1 pathway to achieve the necessary regulation of
the actin cytoskeleton [25].
Watzl and Long [30] examined the localization of CD244
and concluded that it is phosphorylated and recruited into
lipid rafts when NK cells encounter NK-sensitive targets
expressing CD48. Co-engagement of CD244 and an
inhibitory KIR prevents actin-dependent mobilization
of CD244 and its subsequent phosphorylation. Collectively, these studies are beginning to reveal the complex
interplay of signaling molecules involved in NK cell
activation.
NK receptor signaling: development and
effector function
The development of NK cells is remarkably robust and
resilient to disruption. Although some effector functions
are affected, normal numbers of NK cells are present in
mice lacking DAP12, CD3z and FceRIg, individually or
in combination. Furthermore, the ability of NK cells to
develop in the absence of ITAM-mediated signaling has
been confirmed by examining mouse NK cells lacking
both Syk and ZAP70. NK cells from mice lacking both
Syk and ZAP70 killed NK-sensitive tumors such as Yac-1
and RMA-S at levels comparable to wild-type mice,
indicating that non-ITAM-based signaling pathways are
responsible for this function [31]. As anticipated, however, ADCC through CD16 was absent in mice lacking
either FceRIg or both Syk and ZAP70. As NK cells
express both Syk and ZAP70, these kinases appear to
have a redundant function in mice lacking either kinase
alone. As expected, the activating Ly49D receptor was
non-functional in mice lacking DAP12 or both Syk and
ZAP70 [31]. DAP12-deficient mice on the C57BL/6
background are rendered more susceptible to mouse cytomegalovirus (MCMV) infection [32] because Ly49H, an
activating receptor for the m157 MCMV glycoprotein, is
non-functional [33]. Although the mouse NKR–P1C
receptor associates with FceRIg, this receptor retains function in Syk and ZAP70 double-deficient mice, suggesting
that an alternative signaling pathway is used by this receptor [31]. As B- and T-cell development are disrupted in
mice lacking Syk and ZAP70, it is quite surprising that
NK cell development is intact, with loss of only selective
effector functions.
NK cells also develop normally in mice lacking DAP10
[10]. In resting NK cells, NKG2D-mediated functions
were severely compromised; upon activation, however,
NKG2D activity was partially restored by the association
of NKG2D-S with DAP12. NKG2D receptor function in
NK cells does not depend on the presence of DAP12
because NK cells from DAP12-deficient mice and Syk
and ZAP70 double-deficient mice retained the ability to
kill NKG2D ligand-bearing tumors (F Colucci, personal
communication; [33]).
Current Opinion in Immunology 2003, 15:308–314
Normal numbers of NK cells are present in mice lacking
Lck [34], Fyn [34], SLP-76, LAT, SHP-1 and SHIP [21].
Fyn-deficient [34] or SHIP-deficient [21] mice have NK
cells, although the repertoire of inhibitory Ly49 receptors
is affected in these animals. NK cells also develop normally in mice lacking Vav-1, although interestingly they
have diminished cytolytic activity against several tumor
targets [35,36], but retain the ability to make cytokines
[36]. These findings not only implicate Vav-1 as critical
in NK cell-mediated cytotoxicity, but also dissociate the
functions of NK cell degranulation and cytokine production. NK cells develop normally in LAT-deficient mice
[15], possibly because they express the related adaptor
protein non-T-cell activation linker (NTAL; [37]), but
lack CD244-mediated signaling.
As yet, the only defined signaling pathway absolutely
required for NK cell development involves their ability to
respond to IL-15. Disruption of the genes encoding IL15, IL-15a receptor, IL-2 receptor b and IL-2 receptor
common g chain, or Jak-3 (all required for response to IL15) completely abrogated NK cell development, whereas
only rather modest affects on NK cell development were
caused by disruption of IL-2, IL-4, IL-7, or IL-9.
Analysis of NK cells in certain transcription factor genedeficient mice have revealed impairments in NK development or function (reviewed in [38]). Numerous
studies have evaluated the signaling requirement of
‘natural cytotoxicity’ by using pharmacological inhibitors
or transfection of dominant-negative signaling molecules
(reviewed in [4]). On the basis of these studies, Djeu and
colleagues [38] proposed a model of human NK cellmediated cytotoxicity involving a Syk-PI3 kinase-Rac
1-PAK1-MEK1/2-ERK1/2 pathway that is independent
of Ras activation. Although quite compelling, the major
limitation of these and other studies of ‘natural cytotoxicity’ is the lack of identification of the particular NK cell
receptors that are involved in the process.
Conclusions
We are beginning to understand NK cell recognition and
signal transduction in molecular detail. Although many
NK receptors have been discovered in the past few years,
research into understanding their biological relevance and
the regulation between positive and negative signaling
will be areas of intense study in the future. The ITAMbased receptors, integrins and NKG2D can now explain
many of the phenomena referred to as ‘natural killing’;
however, the ability of NK cells from Syk and ZAP70
double-deficient mice to recognize and respond to tumors
lacking ligands for NKG2D still leaves open the question
of which receptors participate in this activity. Nonetheless, recent progress makes it clear that NK cells do not
rely on one omnipresent receptor for their immune functions, rather they are more flexible in their ability to select
from many receptors to accomplish their tasks.
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NK receptor signaling Lanier 313
Acknowledgements
LLL is an American Cancer Society Research Professor and is supported by
National Institutes of Health grants CA89294, CA89189, CA095137 and
CA095137. The author would like to thank Eric Long, Paul Leibson and
Francesco Colucci for discussions and for sharing unpublished findings.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
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These recent reviews [1–4] provide an excellent overview of NK cell
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An intriguing observation demonstrating that alternative splicing can
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The authors describe studies of an unusual dual function KIR that
possesses both activating and inhibitory activities.
24. Rajagopalan S, Fu J, Long EO: Cutting edge: induction of IFN-c
production but not cytotoxicity by the killer cell Ig-like receptor
kir2dl4 (cd158d) in resting NK cells. J Immunol 2001,
167:1877-1881.
The authors suggest that the induction of cytotoxicity and cytokine
production may be dissociated when NK cells are activated through
an unusual KIR.
25. Lou Z, Billadeau DD, Savoy DN, Schoon RA, Leibson PJ: A role for
a RhoA/ROCK/LIM-kinase pathway in the regulation of
cytotoxic lymphocytes. J Immunol 2001, 167:5749-5757.
26. Fassett MS, Davis DM, Valter MM, Cohen GB, Strominger JL:
Signaling at the inhibitory natural killer cell immune synapse
regulates lipid raft polarization but not class I MHC clustering.
Proc Natl Acad Sci USA 2001, 98:14547-14552.
27. Vyas YM, Mehta KM, Morgan M, Maniar H, Butros L, Jung S,
Burkhardt JK, Dupont B: Spatial organization of signal
transduction molecules in the NK cell immune synapses during
MHC class I-regulated noncytolytic and cytolytic interactions.
J Immunol 2001, 167:4358-4367.
28. Vyas YM, Maniar H, Dupont B: Cutting edge: differential
segregation of the SRC homology 2-containing protein
tyrosine phosphatase-1 within the early NK cell immune
synapse distinguishes noncytolytic from cytolytic interactions.
J Immunol 2002, 168:3150-3154.
29. Galandrini R, Tassi I, Mattia G, Lenti L, Piccoli M, Frati L, Santoni A:
SH2-containing inositol phosphatase (SHIP-1) transiently
translocates to raft domains and modulates CD16-mediated
cytotoxicity in human NK cells. Blood 2002, 100:4581-4589.
Current Opinion in Immunology 2003, 15:308–314
314 Lymphocyte activation
30. Watzl C, Long EO: Natural killer cell inhibitory receptors block
actin cytoskeletal-dependent recruitment of 2B4 (CD244) to
lipid rafts. J Exp Med 2003, 197 in press.
31. Colucci F, Schweighoffer E, Tomasello E, Turner M, Ortaldo JR,
Vivier E, Tybulewicz VL, Di Santo JP: Natural cytotoxicity
uncoupled from the Syk and ZAP-70 intracellular kinases.
Nat Immunol 2002, 3:288-294.
Surprising findings that normal numbers of NK cells develop in mice
lacking both Syk and ZAP70 and many effector functions are intact.
32. Sjolin H, Tomasello E, Mousavi-Jazi M, Bartolazzi A, Karre K,
Vivier E, Cerboni C: Pivotal role of KARAP/DAP12 adaptor
molecule in the natural killer cell-mediated resistance to
murine cytomegalovirus infection. J Exp Med 2002,
195:825-834.
A formal demonstration that a DAP12-associated receptor is involved
in vivo in immunity to a viral infection.
33. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL:
Direct recognition of cytomegalovirus by activating and
inhibitory NK cell receptors. Science 2002, 296:1323-1326.
A demonstration that a DAP12-associated receptor Ly49H recognizing a
viral glycoprotein ligand fails to function in DAP12-deficient mice.
34. Lowin-Kropf B, Kunz B, Schneider P, Held W: A role for the src
family kinase Fyn in NK cell activation and the formation of
Current Opinion in Immunology 2003, 15:308–314
the repertoire of Ly49 receptors. Eur J Immunol 2002,
32:773-782.
35. Chan G, Hanke T, Fischer KD: Vav-1 regulates NK T cell
development and NK cell cytotoxicity. Eur J Immunol 2001,
31:2403-2410.
These two papers [35,36] are demonstrations that Vav-1 is important in
NK cell-mediated cytotoxicity against certain tumors.
36. Colucci F, Rosmaraki E, Bregenholt S, Samson SI, Di Bartolo V,
Turner M, Vanes L, Tybulewicz V, Di Santo JP: Functional
dichotomy in natural killer cell signaling. Vav1-dependent
and -independent mechanisms. J Exp Med 2001, 193:1413-1424.
See annotation to [35].
37. Brdicka T, Imrich M, Angelisova P, Brdickova N, Horvath O, Spicka
J, Hilgert I, Luskova P, Draber P, Novak P et al.: Non-T cell
activation linker (NTAL): a transmembrane adaptor protein
involved in immunoreceptor signaling. J Exp Med 2002,
196:1617-1626.
38. Jiang K, Zhong B, Gilvary DL, Corliss BC, Vivier E, Hong-Geller E,
Wei S, Djeu JY: Syk regulation of phosphoinositide 3-kinasedependent NK cell function. J Immunol 2002, 168:3155-3164.
The authors propose a testable biochemical model to explain ‘natural
cytotoxicity’, implicating a Syk-PI3 kinase-Rac 1-PAK1-MeK1/2-ERK1/2
pathway.
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