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Phosphatase-2 (SHP-2)
Region 2-Containing Protein Tyrosine
Activation Via Recruitment of Src Homology
KIR2DL5 Can Inhibit Human NK Cell
Sei-ichi Yusa, Tracey L. Catina and Kerry S. Campbell
http://www.jimmunol.org/content/172/12/7385
doi: 10.4049/jimmunol.172.12.7385
2004; 172:7385-7392; ;
J Immunol
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Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Immunologists All rights reserved.
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The American Association of Immunologists, Inc.,
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KIR2DL5 Can Inhibit Human NK Cell Activation Via
Recruitment of Src Homology Region 2-Containing Protein
Tyrosine Phosphatase-2 (SHP-2)
1
Sei-ichi Yusa, Tracey L. Catina, and Kerry S. Campbell
2
Human NK cells use class I MHC-binding inhibitory receptors, such as the killer cell Ig-like receptor (KIR) family, to discriminate
between normal and abnormal cells. Some tumors and virus-infected cells down-regulate class I MHC and thereby become targets
of NK cells. Substantial evidence indicates that the mechanism of KIR-mediated inhibition involves recruitment of the protein
tyrosine phosphatases, Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2, to two phosphorylated
cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). KIR2DL5 is a type II member of the KIR2D family with
an atypical extracellular domain and an intracytoplasmic domain containing one typical ITIM and one atypical ITIM sequence.
Although KIR2DL5 structure is expressed by
ϳ50% of humans and is conserved among primate species, its function has not been
determined. In the present study, we directly compared functional and biochemical properties of KIR2DL5, KIR3DL1 (a type I
KIR with two ITIMs), and KIR2DL4 (the only other type II KIR, which has a single ITIM) in a human NK-like cell line. Our
results show that KIR2DL5 is an inhibitory receptor that can recruit both SHP-1 and SHP-2, and its inhibitory capacity is more
similar to that of the cytoplasmic domain of KIR2DL4 than KIR3DL1. Interestingly, inhibition of NK cell cytotoxicity by
KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phos-
phatases can block inhibition by KIR3DL1. Therefore, the cytoplasmic domains of type II KIRs (2DL4 and 2DL5) exhibit distinct
inhibitory capacities when compared with type I KIRs (3DL1), due to alterations in the canonical ITIM sequences. The Journal
of Immunology, 2004, 172: 7385–7392.
N
atural killer cells are a subset of lymphocytes that play
an important role in innate immunity by directing cyto-
lytic attack toward class I MHC (MHC-I)-deficient tu-
mor cells and virus-infected cells (1, 2). NK cells also contribute
to acquired immunity by secreting various cytokines, including
IFN-
␥ (1, 2). NK cell activation is controlled by a balance between
activating and inhibitory receptors (3). Although T and B cells are
activated by single clonotypic surface Ag receptors, activation of
NK cells is derived from a combination of numerous positive sig-
nals generated by many receptors engaging with ligands on target
cell surfaces, including CD16, activating forms of killer cell Ig-
like receptors (KIRs),
3
activating forms of CD94/NKG2 dimers,
NKG2D, and natural cytotoxicity receptors (NKp30, NKp44, and
NKp46). These potent activating receptors associate noncovalently
with dimers of accessory chains, named TCR-
, Fc⑀RI-␥, DAP12,
or DAP10, which contain the immunoreceptor tyrosine-based ac-
tivation motif or a YxxM motif for positive signaling (4, 5). Con-
versely, NK cell activation is abrogated by MHC-I-binding inhib-
itory receptors that have a long cytoplasmic tail containing
immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (6). In-
hibitory KIRs are the major classical MHC-I-binding inhibitory
receptors expressed on human NK cells and a subset of T cells (7).
Engagement of these inhibitory receptors with appropriate MHC-I
ligands has been shown to block natural cytotoxicity, Ab-depen-
dent cellular cytotoxicity (8, 9), and adhesion toward target cells
(10). Thus, inhibitory KIRs are important not only for tumor sur-
veillance, but also for immunological tolerance to discriminate be-
tween normal and abnormal cells.
ITIM sequences are found in many inhibitory receptors, and the
critical role of ITIM sequences on negative signaling has been well
established (11, 12). Phosphorylated ITIM sequences recruit Src
homology region 2 (SH2)-containing negative effector phospha-
tases, such as SH2-containing protein tyrosine phosphatase-1
(SHP-1), SHP-2, and SH2-containing inositol 5
Ј-phosphatase
(SHIP). Substantial evidence indicates that SHP-1 is involved in
KIR-mediated inhibition, including SHP-1 binding and activation
by KIR ITIM phosphopeptides, recruitment of SHP-1 to tyrosine-
phosphorylated KIRs in NK cells, and blockade of KIR inhibition
with a dominant-negative (DN) form of SHP-1 (8, 9, 13–19). In
addition, we have recently used similar approaches to demonstrate
that KIR inhibition in human NK cells also involves recruitment of
SHP-2 (20). In contrast, KIR inhibition does not appear to involve
SHIP (17). Thus, both SHP-1 and SHP-2 protein tyrosine phos-
phatases (PTP) play roles in inhibitory KIR function. However,
how KIRs selectively use these phosphatases and whether they
function through dephosphorylation of distinct substrates are
unknown. KIR2DL5 (2DL5) is a recently described member of the
Division of Basic Science, Fox Chase Cancer Center, Institute for Cancer Research,
Philadelphia, PA 19111
Received for publication July 22, 2003. Accepted for publication April 14, 2004.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
1
This work was supported by Grant CA083859 to K.S.C. from the National Institutes
of Health. The research was also supported in part by National Institutes of Health
Centers of Research Excellence Grant CA06927 and an appropriation from the Com-
monwealth of Pennsylvania. Its contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National Cancer Institute.
2
Address correspondence and reprint requests to Dr. Kerry S. Campbell, Fox Chase
Cancer Center, Institute for Cancer Research, 333 Cottman Avenue, Philadelphia, PA
19111. E-mail address: kerry.campbell@fccc.edu
3
Abbreviations used in this paper: KIR, killer cell Ig-like receptor; DN, dominant
negative; EGFP, enhanced GFP; GFP, green fluorescence protein; ITIM, immunore-
ceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch
motif; PTP, protein tyrosine phosphatase; SAP, SLAM-associated protein; SH2, Src
homology 2; SHIP, SH2-containing 5
Ј-inositol phosphatase; SHP, SH2-containing
PTP; SLAM, signaling lymphocyte activation molecule.
The Journal of Immunology
Copyright © 2004 by The American Association of Immunologists, Inc.
0022-1767/04/$02.00
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