Role of chemokines in the biology of natural killer cells
Michael J. Robertson
Bone Marrow and Stem Cell Transplantation Program and Division of Hematology/Oncology, Indiana University
School of Medicine, Indianapolis
Abstract: Natural killer (NK) cells participate in
innate and adaptive immune responses to obligate
intracellular pathogens and malignant tumors. Two
major NK cell subsets have been identified in hu-
mans: CD56dim CD16ⴙ and CD56bright CD16ⴚ.
Resting CD56dim CD16ⴙ NK cells express
CXCR1, CXCR2, CXCR3, CXCR4, and CX3CR1
but no detectable levels of CC chemokine recep-
tors on the cell surface. They migrate vigorously in
response to CXCL12 and CXC3L1. In contrast,
resting CD56bright CD16ⴚ NK cells express little
CXCR1, CXCR2, and CXC3R1 but high levels of
CCR5 and CCR7. Chemotaxis of CD56bright
CD16ⴚ NK cells is stimulated most potently by
CCL19, CCL21, CXCL10, CXCL11, and CXCL12.
Following activation, NK cells can migrate in re-
sponse to additional CC and CXC chemokines. Cy-
tolytic activity of NK cells is augmented by CCL2,
CCL3, CCL4, CCL5, CCL10, and CXC3L1. More-
over, proliferation of CD56dim CD16ⴙ NK cells is
costimulated by CCL19 and CCL21. Activated NK
cells produce XCL1, CCL1, CCL3, CCL4, CCL5,
CCL22, and CXCL8. Chemokines secreted by NK
cells may recruit other effector cells during im-
mune responses. Furthermore, CCL3, CCL4, and
CCL5 produced by NK cells can inhibit in vitro
replication of HIV. CCL3 and CXL10 expression
appear to be required for protective NK cell re-
sponses in vivo to murine cytomegalovirus or
Leishmania major, respectively. Moreover, NK
cells participate in the in vivo rejection of trans-
duced tumor cells that produce CCL19 or CCL21.
Thus, chemokines appear to play an important role
in afferent and efferent NK cell responses to in-
fected and neoplastic cells. J. Leukoc. Biol. 71:
173–183; 2002.
Key Words: chemotaxis 䡠 cytotoxicity 䡠 proliferation
INTRODUCTION
Natural killer (NK) cells, such as T and B cells, are one of the
major lymphocyte subsets that have been identified in all
vertebrate species examined [1–3]. Unlike T and B lympho-
cytes, however, NK cells do not productively rearrange T-cell
receptor or immunoglobulin genes and do not appear to express
highly variable, antigen-specific receptors. Nevertheless, NK
cells can discriminate between normal cells and neoplastic or
virus-infected cells [1–3]. NK cells participate in innate im-
mune responses that can inhibit intracellular pathogens while
antigen-specific T- and B-cell responses are generated [4 – 6].
Moreover, NK cells secrete cytokines, such as interferon-␥
(IFN-␥), which promote the differentiation of activated CD4 T
cells into Th1 helper effector cells [4, 5, 7]. NK cells can also
contribute to the elimination of infected cells during the effec-
tor phase of adaptive immune responses [1–3]. NK cells can
recognize and destroy cancer cells that have evaded cytotoxic
T lymphocytes (CTL) [8]. Thus, NK cells participate in innate
and adaptive immune responses to intracellular pathogens and
malignant tumors.
The cytolytic activity of NK cells is clearly distinguishable
from that mediated by typical CTL: It occurs spontaneously
(i.e., in the absence of deliberate, prior immunization) and does
not require expression of syngeneic major histocompatibility
complex (MHC) antigens by target cells. Recently, the molec-
ular basis for target-cell recognition by human and murine NK
cells has been elucidated [2, 8 –10]. Unlike CTL, NK cells do
not appear to express one dominant receptor that dictates the
specificity of cytolysis. Rather, triggering of NK cell cytotox-
icity reflects a balance between activating and inhibitory sig-
nals mediated by cell-surface receptors that belong to several
different gene families. Inhibitory MHC class I receptors have
a central role in current paradigms of target-cell recognition by
NK cells [2, 8 –10]. Ligation of these inhibitory receptors by
specific MHC class I allotypes delivers a dominant-negative
signal to NK cells that prevents natural killing. Down-regula-
tion of MHC class I molecules on the target-cell surface, which
commonly occurs during viral infection or neoplastic transfor-
mation, releases the NK cell from inhibitory signals and allows
lysis of the aberrant target cell. Positive signals for cytolysis
are provided by ligation of several activating receptors (e.g.,
CD2, CD16, NKR-P1, 2B4, NKp30, NKp44, and NKp46)
expressed by NK cells [2, 9, 10]. However, the contribution of
these putative activating receptors to triggering NK cytolysis in
vivo has not been well-defined.
Like T cells, NK cells are heterogeneous with respect to
functional activity and cell-surface antigen expression [11–14].
Two major NK cell subsets have been identified in humans.
CD56dim NK cells, comprising about 90% of peripheral blood
NK cells, express the CD16 antigen at high density but rela-
Correspondence: Michael J. Robertson, M.D., Bone Marrow and Stem Cell
Transplantation Program, 1044 W. Walnut Street, Room R4-202, Indianapolis,
IN 46202. E-mail: mjrobert@iupui.edu
Received November 1, 2001; revised November 29, 2001; accepted Novem-
ber 30, 2001.
Journal of Leukocyte Biology Volume 71, February 2002 173
tively low levels of CD56. Freshly isolated, unstimulated
CD56dim NK cells mediate natural killing and antibody-depen-
dent cellular cytotoxicity (ADCC). CD56dim NK cells express ␤
␥ common chains of the interleukin (IL)-2 and IL-15 receptors
and demonstrate augmented cytotoxicity, proliferation, and cy-
tokine secretion after stimulation with IL-2 or IL-15 [11–13,
15]. However, CD56dim NK cells produce relatively little
IFN-␥ after stimulation with IL-2 or IL-15 in combination with
IL-12. CD56bright NK cells express high-affinity IL-2 receptor
␣ ␤ ␥ heterotrimers but little or no CD16. CD56bright NK cells
proliferate vigorously in response to IL-2 alone [11–13] and
produce abundant amounts of IFN-␥ after stimulation with IL-2
or IL-15, together with IL-12. In contrast, CD56bright NK cells
exhibit weak cytolytic activity when freshly isolated. These
observations support the hypothesis that CD56bright NK cells,
like CD4 T cells, predominantly regulate other cells through
cytokine production [14, 16]. In contrast, CD56dim NK cells,
like CD8⫹ CTL, are terminally differentiated cytotoxic-
effector cells.
The CD56bright and CD56dim NK cell subsets can be reliably
distinguished only for resting human NK cells. The CD56
antigen is up-regulated on CD56dim NK cells following activa-
tion in vitro or in vivo [17–21]. Thus, the density of CD56 on
the cell surface cannot be used to discriminate unstimulated
CD56bright NK cells from activated CD56dim NK cells. More-
over, subsets analogous to CD56bright and CD56dim NK cells in
humans have not been identified in mice or other species. It
should be noted that murine NK cells do not express CD56, so
this molecule cannot be required for NK cell function in vivo.
To mediate their cytolytic function effectively, NK cells
must be recruited to the site of infected or neoplastic cells.
Moreover, to regulate the adaptive immune response, cytokine-
secreting NK cells must be in intimate proximity to antigen-
stimulated T and/or B cells. Nevertheless, until recently, very
little was known about the regulation of NK cell migration and
trafficking. Work done in several laboratories over the past few
years has implicated chemokines as key regulators of NK cell
migration and function.
Chemokines play a crucial role in coordinating adaptive
immune responses. Chemokines regulate the migration of im-
mature lymphoid progenitor cells, the recirculation of mature
naive T and B lymphocytes, and the homing of antigen-specific
effector T cells. Chemokines also control the migration of
antigen-presenting cells, including dendritic cells and cells of
monocyte/macrophage lineage [22–27]. Other important phys-
iologic and pathophysiologic activities of chemokines include
inhibition or promotion of angiogenesis, regulation of tumor
metastasis, inhibition of hematopoietic progenitor cell prolif-
eration, and modulation of HIV infection. A detailed discus-
sion of chemokine biology is beyond the scope of this review.
Interested readers are referred to recent review articles devoted
to chemokines and their receptors [22–28].
Inconsistency and bewildering complexity have character-
ized the nomenclature of chemokines and their receptors in the
past. It is not uncommon to encounter from three to more than
five different synonyms being used in the literature to refer to
the same chemokine. Recently, a uniform and widely accepted
nomenclature has been adapted [23, 27, 29]. Common syn-
onyms for some chemokines that have been shown to affect NK
cell function are summarized in Table 1.
CHEMOKINE RECEPTORS EXPRESSED BY
NK CELLS
The expression of chemokine receptors by human NK cells is
a subject of controversy. The two most comprehensive studies
that have been published to date provide contradictory results,
particularly with respect to the CXC chemokine receptors.
Campbell et al. [30] found that most human NK cells express
high levels of CXCR1, CXCR4, and CX3CR1; CXCR2 and
CXCR3 were expressed at lower levels. Several other groups
have also described expression of CXCR1 and CXCR2 [31, 32]
or CX3CR1 [33, 34] by resting human NK cells. In contrast,
TABLE 1. Synonyms for Selected Chemokines
with NK Cell Activity

CHEMOKINES AND THEIR RECEPTORS Chemokine Synonyms

XCL1 Lymphotactin ␣, SCM-1␣, ATAC

Chemokines are a group of at least 47 related proteins, making XCL2 Lymphotactin ␤, SCM-1␤, ATAC
them the largest family of cytokines known [22–27]. Depending CCL1 I-309, TCA3
on the number and spacing of conserved cysteine residues in CCL2 MCP-1, MCAF, JE
their amino acid sequence, chemokines have been classified CCL3 MIP-1␣
CCL4 MIP-1␤
into four major groups: the CXC (or ␣), CC (or ␤), CX3C, and
CCL5 RANTES
C subfamilies. The CXC and CC subfamilies have been sub- CCL7 MCP-3
divided further according to structural homologies and biolog- CCL8 MCP-2
ical activities. Chemokines exert their biologic effects by bind- CCL19 MIP-3␤, ELC, CK␤-11, Exodus-3
ing to specific cell-surface receptors. The chemokine receptors, CCL20 MIP-3␣, LARC, Exodus-1, ST38
CCL21 6Ckine, Exodus-2, SLC, CK␤-9, TCA4
which have also been classified into four subfamilies, are
CCL22 MDC, STCP-1, ABCD-1
G-protein-coupled seven-transmembrane-spanning molecules. CXCL8 IL-8
A single chemokine can bind to more than one receptor, and a CXCL9 Mig
given receptor can interact with multiple chemokines. Together CXCL10 IP-10, crg-2
with the large number of chemokines and receptors, this poses CXCL11 I-TAC, IP-9, H174, ␤-R1
CXCL12 SDF-1␣, SDF-1␤, PBSF
a formidable challenge for investigators seeking to elucidate
CX3CL1 Fractalkine, neurotactin
the physiologic role of chemokines in vivo.

174 Journal of Leukocyte Biology Volume 71, February 2002 http://www.jleukbio.org

Inngjerdingen et al. [35] found that purified, resting human NK
cells expressed CXCR4 but not CXCR1, CXCR2, CXCR3, or
CX3CR1. It is not clear why Inngjerdingen et al. [35] failed to
detect CXCR1, CXCR2, and CX3CR1 on resting human NK
cells. It is possible that levels of these chemokine receptors
were down-regulated during the isolation of purified NK cells
by their methods; this phenomenon has been noted by another
group [36].
The published data are more consistent with respect to NK
cell expression of the CC chemokine receptors. As assessed by
flow cytometry using specific antibodies, CCR1, CCR2, CCR3,
CCR4, CCR5, CCR6, CCR7, CCR8, and CCR9 are not ex-
pressed at significant levels on the surface of most resting
human NK cells [30, 35, 37]. CCR2, CCR4, CCR5, and CCR8
are expressed by human NK cells after in vitro activation with
IL-2 or IL-15 [35, 37, 38].
Recent studies have clarified the expression of CCR7 and
response to the CCR7 ligands, CCL19 and CCL21, by human
NK cells. Several groups have demonstrated that CCL19 and
CCL21 do not stimulate significant chemotaxis of resting pe-
ripheral blood NK cells [39 – 41]. Moreover, message for
CCR7, as assessed by Northern blot or reverse transcriptase-
polymerase chain reaction (RT-PCR) analysis, was not de-
tected in resting NK cells [40, 41]. In contrast, Kim et al. [42]
found that CCL19 and CCL21 stimulated the migration of the
CD16⫺ subset of cord blood and adult peripheral blood NK
cells. CD56bright CD16⫺ NK cells normally comprise only
⬃10% of the total peripheral blood NK cell population, and
selective chemotaxis of this subset is obscured readily by the
relatively high, spontaneous migration of the much more nu-
merous CD56dim CD16⫹ NK cells [39]. However, Kim et al.
[42] isolated adult and cord blood NK cells by positive selec-
tion using CD56 beads, which greatly enriches the proportion
of CD56bright CD16⫺ NK cells among the total NK cell pop-
ulation [43]. Subsequent work has confirmed that CD16⫺ but
not CD16⫹ resting human NK cells express CCR7 on the cell
surface and migrate vigorously in response to CCL19 and
CCL21 [30]. Results from the author’s laboratory (unpublished
results) are concordant with those of Campbell et al. [30] with
respect to expression of CCR6 and CCR7 by resting CD56bright
and CD56dim NK cells.
In contrast to results of others [30, 41] and our unpublished
data, Inngjerdingen et al. [35] have demonstrated that the
majority of resting human NK cells expresses CCR7. However,
Inngjerdingen et al. [35] used a polyclonal antibody recogniz-
ing the carboxy terminus of CCR7 to stain permeabilized NK
cells. Thus, the CCR7 molecules detected by this method may
be located intracellularly rather than on the cell surface.
In addition to CCR7, other chemokine receptors are ex-
pressed differentially by the CD56bright CD16⫺ and CD56dim
CD16⫹ subsets of human NK cells (Table 2). Unlike the great
majority of resting NK cells, the rare CD56bright CD16⫺ subset
does not express CXCR1, CXCR2, or CX3CR1 but does ex-
press CCR5 [30]. As expected, based on the known biology of
chemokine receptors, chemotaxis of NK cells stimulated by
chemokines is inhibitable by Bordetella pertussis toxin [42, 44,
45]. Chemokine signaling in NK cells involves several guanine
nucleotide-binding proteins and leads to intracellular calcium
ion mobilization [45– 48].
REGULATION OF NK CELL MIGRATION BY
CHEMOKINES
Numerous chemokines have been shown to stimulate the mi-
gration of NK cells as determined by in vitro chemotaxis assays
(Tables 3 and 4). Results with the CXC chemokines agree
well with the data on CXC chemokine receptor expression by
NK cells. Thus, resting human NK cells have been found to
migrate in response to known ligands for CXCR3 (CXCL9,

TABLE 2. Expression of Chemokine Receptors by Resting Human NK Cells

Chemokine Receptor CD56dimCD16⫹ NK Cells CD56brightCD16-NK Cells Unfractionated NK Cellsa References

XCR1 NR NR NR
CCR1 0b 0 0 [30, 35]
CCR2 0 0 0 [30, 35, 37]
CCR3 0 0 0 [30, 35]
CCR4 ⫹/⫺ 0 0 [30, 35]
CCR5 0 ⫹ 0 [30, 35, 37]
CCR6 0 0 0 [30, 35]
CCR7 0 ⫹ ⫹/⫺ [30, 35]
CCR8 NR NR 0 [35]
CCR9 0 0 NR [30]
CCR10 NR NR NR
CCR11 NR NR NR
CXCR1 ⫹ 0 ⫹ [30–32]
CXCR2 ⫹ 0 ⫹ [30–32]
CXCR3 ⫹ ⫹ ⫹/⫺ [30, 35, 104]
CXCR4 ⫹ ⫹ ⫹ [30, 35]
CXCR5 0 0 0 [30, 35]
CXCR6 0 0 NR [30]
CX3CR1 ⫹ ⫹/⫺ ⫹ [30, 33–35]
a
Unfractionated human peripheral blood NK cell preparations are expected to contain ⬃10% CD56bright NK cells and ⬃90% CD56dim NK cells.
b
⫹, positive results reported; 0, negative results reported; ⫹/⫺, equivocal or contradictory results reported; NR, results not reported.

Robertson Chemokine role in biology of NK cells 175

 TABLE 3. Migration of Resting NK Cells in Response to Chemokines

Chemokine Total NK cells CD56dim/CD16⫹ NK cells CD56bright/CD16⫺ NK cells References

XCL1 ⫹a NR NR [50, 54]

CCL1 0 NR NR [35]
CCL2 ⫹/⫺ ⫹/⫺ ⫹/⫺ [30, 34, 36, 44, 50]
CCL3 ⫹ ⫹ ⫹ [36, 51]
CCL4 ⫹ 0 ⫹/⫺ [30, 36]
CCL5 ⫹ 0 ⫹ [30, 36]
CCL7 ⫹/⫺ ⫹/⫺ ⫹ [30, 36, 44]
CCL8 ⫹/⫺ NR NR [36, 44]
CCL17 0 0 NR [34]
CCL19 ⫹/⫺ 0 ⫹ [30, 35, 40–42]
CCL20 ⫹/⫺ ⫹/⫺ ⫹/⫺ [30, 35, 40]
CCL21 0 0 ⫹ [30, 39, 40, 42]
CCL22 ⫹/⫺ 0 0 [30, 35]
CCL25 NR 0 0 [30]
CXCL1 ⫹/⫺ NR NR [35, 36]
CXCL8 ⫹/⫺ ⫹ 0 [30, 35, 36]
CXCL9 ⫹ NR NR [49]
CXCL10 ⫹ ⫹/⫺ ⫹ [30, 35, 36]
CXCL11 NR ⫹/⫺ ⫹ [30]
CXCL12 ⫹ ⫹ ⫹ [30, 35, 39, 42]
CX3CL1 ⫹ ⫹ 0 [30, 34, 35]
a
See key to symbols in footnotes to Table 2.

CXCL10, and CXCL11) and CXCR4 (CXCL12) [30, 35, 36,
39, 42, 49]. Furthermore, chemotaxis of resting NK cells is
stimulated by XCL1 and CX3CL1 [30, 35, 50]. Although
CXCR1 and CXCR2 appear to be expressed by most resting
human NK cells [30 –32], the responsiveness of the latter to
CXCL1 or CXCL8 is a subject of controversy. Some investiga-
tors have shown that resting NK cells can migrate in response
to CXCL1 [35] or CXCL8 [30]; other investigators have found
these chemokines to have inconsistent, donor-dependent ef-
fects on resting NK cells [36]. Furthermore, CXCL8 may not
stimulate the chemotaxis of human NK cells that have been
activated in vitro [35, 47].
Resting human NK cells also migrate in response to several
CC chemokines, including CCL2, CCL3, CCL4, CCL5, CCL7,
and CCL8 [35, 36, 44, 51], although known receptors for the
latter are generally undetectable on most resting NK cells [30,
35, 37]. However, results with the CC chemokines are not
consistent in the published literature: Some investigators have
demonstrated positive findings using activated but not resting
NK cells [44, 47]. It is possible that some of the known CC
chemokine receptors are actually expressed on the surface of
resting NK cells but at levels below the limits of detection by
routine flow cytometry. Alternatively, resting NK cells may
express as-yet uncharacterized novel receptors for some of the

TABLE 4. Chemokines Reported to Stimulate Migration of Activated NK Cells

Chemokine Cell preparation Stimulusa References

XCL1 Polyclonal human and murine NK cells; human NK clones IL-2; IL-2 ⫹ SC [45, 50, 54]
CCL1 Polyclonal human NK cells IL-2 [35, 52]
CCL2 Polyclonal human NK cells and NK clones IL-2; IL-2 ⫹ SC [35, 44, 47]
CCL3 Human NK clones IL-2 [47, 105]
CCL4 Human NK clones IL-2 [47]
CCL5 Human NK clones IL-2 [47, 105]
CCL7 Polyclonal human NK cells and NK clones IL-2; IL-2 ⫹ SC [44, 47]
CCL8 Polyclonal human NK cells and NK clones IL-2; IL-2 ⫹ SC [44, 47]
CCL17 Polyclonal human NK cells IL-2 [35, 52]
CCL19 Polyclonal human NK cells; NKL cellsb IL-2; LCM ⫹ lono [35, 40, 42]
CCL21 Polyclonal human NK cells; NKL cells IL-2; LCM ⫹ lono [40, 42]
CCL22 Polyclonal human NK cells IL-2; IL-2 ⫹ SC [35, 52, 53]
CXCL1 Polyclonal human NK cells IL-2 [35]
CXCL8 Polyclonal human NK cells IL-2 [46]
CXCL10 Polyclonal human NK cells IL-2 [35, 45]
CXCL12 Polyclonal human NK cells; NKL cells IL-2 [35, 40]
CX3CL1 Polyclonal human NK cells IL-2 [35]
a
SC, stimulator cells (e.g., irradiated B lymphoblastoid cell lines); LCM ⫹ lono, leukocyte conditioned medium plus ionomycin.
b
NKL is an IL-2-dependent neoplastic human NK cell line [106].

176 Journal of Leukocyte Biology Volume 71, February 2002 http://www.jleukbio.org

CC chemokines. After in vitro activation, human NK cells TABLE 5. Effect of Chemokines on NK Cell Cytotoxicity
up-regulate CCR2, CCR4, CCR7, and CCR8 [35, 37, 38, 40,
52] and demonstrate increased chemotactic responses to Resting NK Activated
Chemokine Cells NK Cells References
known ligands of these receptors, including CCL1, CCL2,
CCL3, CCL4, CCL5, CCL7, CCL8, CCL19, CCL21, and CCL2 ⫹a NR [36,57,58]
CCL22 [35, 40, 44, 47, 53]. CCL3 ⫹ NR [36,57,58,69]
Differences in the chemotactic responses of resting CCL4 ⫹ NR [36,57,58]
CD56bright and CD56dim NK cells correlate well with known CCL5 ⫹ NR [36,57,58]
CCL19 0 0 [40]
differences in their expression of chemokine receptors [30]. CCL20 0 0 [40]
Compared with CD56dim NK cells, CD56bright NK cells express CCL21 0 0 [40]
higher levels of CXCR3 and respond more vigorously to CXCL1 0 NR [36,57]
CXCL10 and CXCL11. Conversely, CD56bright NK cells ex- CXCL2 0 NR [36,57]
press little or no CXCR1, CXCR2, and CX3CR1 and do not CXCL4 0 NR [36,57]
CXCL8 0 NR [36,58]
migrate in response to CXCL8 or CX3CL1. As discussed CXCL10 ⫹ NR [36]
above, CD56bright NK cells but not CD56dim NK cells express CX3CL1 ⫹ NR [33]
CCR7 and respond to CCL19 and CCL21 [30, 42]. a
In contrast to the abundant in vitro studies, published data See key to symbols in footnotes to Table 2.
on in vivo migration of NK cells in response to chemokines are
sparse. Intraperitoneal (i.p.) injection of murine XCL1 induces
transient influx of lymphocytes into the peritoneal cavity [54]. found to augment ADCC or induced the lysis of NK-resistant
The majority of these lymphocytes are mature NK cells. How- targets by human NK cells. CX3CL1 has also been shown to
ever, freshly isolated murine NK cells did not migrate in vitro modestly increase NK cell cytotoxicity toward NK-sensitive
in response to XCL1 [54]. Therefore, additional factors, per- target cells [33].
haps induced by the local trauma of i.p. injection, may act in Maghazachi et al. [58] have shown that CCL2, CCL3, CCL4,
concert with XCL1 to stimulate chemotaxis of murine NK cells and CCL5 can augment cytotoxicity of enriched CD56⫹ hu-
in vivo. As discussed in detail below, CCL3 promotes in vivo man NK cells. In contrast to the results of Taub et al. [36],
migration of activated NK cells into the livers of mice infected these investigators found that the effects of CCL2, CCL3, and
with murine cytomegalovirus (MCMV) [6, 55]. CCL5 were comparable with those of optimal concentrations of
IL-2 and that chemokines could stimulate lysis of NK-sensitive
and NK-resistant target cells.
REGULATION OF NK CELL CYTOTOXICITY The mechanisms by which chemokines augment NK cell
BY CHEMOKINES cytolytic activity have not been fully elucidated. Lysis of target
cells by NK cells occurs in three phases [1, 2, 9, 10]. First, NK
NK cells mediate antibody-dependent and -independent lysis cells must bind to potential target cells via interactions be-
of target cells [1, 2, 9, 10]. Resting NK cells can lyse antibody- tween NK cell-surface adhesion molecules [e.g., lymphocyte
coated target cells by ADCC. The receptor on NK cells that function-associated antigen-1 (LFA-1) and CD2] and their
triggers ADCC is a multimolecular complex composed of cognate target-cell ligands [e.g., intercellular adhesion mole-
CD16, a low-affinity receptor for the Fc portion of immuno- cules (ICAM)-1, -2, and -3 and CD58]. Next, positive signals
globulin, in noncovalent association with homodimers or het- from ligation of activating receptors (e.g., CD16) must outweigh
erodimers of the ␨ family of signaling molecules. Resting NK negative signals from ligation of inhibitory receptors. Finally,
cells can also spontaneously lyse NK-sensitive target cells by NK cells must express apoptosis-inducing ligands (e.g., CD95
an antibody-independent process known as natural killing or ligand) and/or must discharge their cytotoxic granules against
NK activity [1, 2, 9, 10]. Sensitivity to natural killing is the the target-cell membrane [59]. NK cell cytotoxic granules
property of certain virus-infected and neoplastic-hematopoietic contain perforin and granzymes, which can induce apoptosis
cells; most normal cells and malignant epithelial cells are and necrosis of target cells.
NK-resistant. Nevertheless, after exposure to exogenous cyto- CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CXCL10, and
kines (such as IL-2, IL-12, or IL-15), NK cells can lyse solid CX3CL1 have been shown to promote cytotoxic granule release
tumor cells that are resistant to lysis by unstimulated NK cells by resting polyclonal human NK cells or NK cell clones [33,
[15, 18, 56]. This cytolytic activity has been called lympho- 36, 47]. Concentrations of chemokines that stimulate granule
kine-activated killer (LAK) activity. exocytosis were similar to those that enhance NK cell cytolytic
Relatively few chemokines have been shown to enhance the activity. Thus, chemokines may augment NK cell lysis of target
cytolytic activity of NK cells (Table 5). Taub et al. [36, 57] cells, in part, by facilitating the discharge of NK cell cytotoxic
found that CCL3 and CXCL10 consistently augmented the lysis granules. Augmentation of NK cell cytotoxicity by CX3CL1
of NK-sensitive K562 cells by purified, human NK cells. was not associated with up-regulation of LFA-1, CD2, or other
Enhancement of natural killing by these cytokines was inferior adhesion molecules on NK cells [33]. However, several CC
to that produced by optimal concentrations of IL-2. CCL2, chemokines known to augment NK cell cytotoxicity have been
CCL4, and CCL5 were also found to stimulate greater levels of found to induce redistribution of adhesion molecules on the NK
natural killing, albeit less consistently and in a donor-depen- cell surface [37]. Nevertheless, the effects of chemokines on
dent fashion. Unlike IL-2, none of these chemokines were NK cell adhesion-molecule expression and their conjugate

Robertson Chemokine role in biology of NK cells 177

formation with target cells have not been described in detail
and merit further investigation. Moreover, it is currently not
known whether chemokines affect signals that are transduced
after ligation of activating or inhibitory NK cell receptors.
REGULATION OF NK CELL PROLIFERATION
BY CHEMOKINES
Human NK cells can be induced to proliferate in response to
IL-2, IL-4, IL-7, IL-12, and IL-15 [15, 18, 60, 61]. However,
NK cell proliferation to IL-2 and IL-15 is about tenfold greater
than proliferation to other mitogenic cytokines. Thus, signals
mediated through the common IL-2/IL-15 ␤ ␥ receptor appear
to provide the strongest proliferative stimulus for human NK
cells. Like proliferation of T and B lymphocytes, the prolifer-
ation of NK cells appears to require costimulatory signals as
well as primary mitogenic signals. Costimulation of NK cell
proliferation can be provided by soluble cytokines, ligation of
defined cell-surface receptors, or contact with certain stimula-
tor cells [60 – 64].
None of the chemokines that have been tested so far, in-
cluding CCL2, CCL3, CCL4, CCL5, CCL19, CCL20, CCL21,
and CXCL8, have been found to stimulate the proliferation of
purified, resting NK cells [40, 58]. CCL2, CCL3, CCL4, and
CCL5 can induce the proliferation of nylon-wool column-non-
adherent peripheral blood lymphocytes (PBL), which contain
mostly T and NK cells [58]. Purified CD4 and CD8 T cells did
not proliferate in response to CC chemokines. Furthermore,
CCL3- and CCL5-induced proliferation of PBL was abrogated
by the presence of neutralizing anti-IL-2 antibody. Thus, it has
been speculated that CC chemokines can stimulate T-cell
secretion of IL-2, which then indirectly stimulates the prolif-
eration of NK cells [58].
Little has been published regarding the ability of chemo-
kines to costimulate NK cell proliferation in response to pri-
mary mitogens. The two known CCR7 ligands, CCL19 and
CCL21, can costimulate IL-2-induced proliferation of CD56dim
NK cells [40]. Such costimulation was dose-dependent and was
of moderate magnitude. No effect of CCL19 or CCL21 on the
more robust proliferation of CD56bright NK cells in response to
IL-2 was detected [40]. Moreover, CCL20 in doses as high as
1000 ng/ml did not affect IL-2-induced proliferation of
CD56dim or CD56bright NK cells.
CHEMOKINES PRODUCED BY NK CELLS
In addition to responding to numerous chemokines, NK cells
have been found to produce several chemokines (Table 6).
Human peripheral blood NK cells cultured in the absence of
deliberate stimuli can spontaneously produce CCL4, CCL5,
and CCL22 in vitro [37, 65– 68]. Unstimulated normal human
NK cells express mRNA for CCL3 [66], but appear to produce
little if any CCL3 protein [65, 69]. Resting human NK cells
also express mRNA for XCL1 [35, 70], but XCL1 protein was
not detected in the cytoplasm of unstimulated murine NK cells
[54]. CD56bright CD16⫺ NK cells isolated from human uterine
decidua spontaneously express CXCL8 mRNA and secrete
178 Journal of Leukocyte Biology Volume 71, February 2002
TABLE 6. Production of Chemokines by NK Cellsa
Resting NK Activated
Chemokine Cells NK Cells References
XCL1 0b ⫹ [54]
CCL1 NR ⫹ [74]
CCL3 ⫹/⫺ ⫹ [37, 65, 66, 68, 69, 73]
CCL4 ⫹ ⫹ [37, 65, 66, 68, 72, 73]
CCL5 ⫹ ⫹ [37, 65–67]
CCL22 ⫹ ⫹ [67]
CXCL8 ⫹c ⫹ [71, 75, 76]
a
Chemokines included in this table are those for which protein production
by NK cells has been reported.
b
See key to symbols in footnotes to Table 2.
c
Results pertain to freshly isolated uterine decidual CD56bright/CD16-NK
cells.
CXCL8 protein [71]. It is currently not known whether periph-
eral blood CD56bright CD16⫺ or CD56dim CD16⫹ NK cells
spontaneously produce CXCL8.
After in vitro activation, NK cells produce greater amounts
of CCL4, CCL5, CCL22, and CXCL8 and also produce XCL1,
CCL1, and CCL3 [37, 54, 65– 69, 72–76]. Based on these
results, it is expected that T cells, B cells, NK cells, neutro-
phils, and several other cell types could be attracted to the
vicinity of activated NK cells. In fact, little has been published
about the ability of activated NK cells to attract other cells in
vitro or in vivo. Supernatants from activated human NK cells
stimulate the in vitro migration of CD4 T cells, CD8 T cells,
and neutrophils [76]. CXCL8 produced by activated NK cells
was found to be partially but not completely responsible for the
observed T-cell chemotaxis. Nieto et al. [37] have shown that
IL-2-activated human NK cells can induce the chemotaxis of
other NK cells. Moreover, interaction between NK cells and
NK-sensitive K562 target cells stimulated greater production
of CCL3, CCL4, and CCL5 [37, 66] and a concomitant increase
in the migration of bystander NK cells [37]. These data suggest
that NK cell interaction with target cells can stimulate secre-
tion of chemokines that promote the recruitment of additional
NK cells to sites of infected or transformed cells.
CCR5 is a coreceptor for macrophage-tropic (M-tropic)
strains of HIV-1 [25]. Ligands for CCR5, including CCL3,
CCL4, and CCL5, have been shown to inhibit the infection of
human cells by M-tropic HIV-1 strains. Because activated
human NK cells can produce CCL3, CCL4, and CCL5, it is
possible that NK cells could be manipulated with therapeutic
intent in the treatment of HIV-1 infection. Indeed, activated
NK cells from HIV-infected persons have been shown to sup-
press HIV replication in autologous lymphocytes in vitro [66].
Furthermore, HIV-1 replication in normal PBL is inhibited
potently in vitro by supernatants of activated NK cells from
HIV-infected or normal control donors [65]. The effects of
activated NK cells or their supernatants on HIV replication are
partially but not completely reversed by the presence of neu-
tralizing antibodies to CCL3, CCL4, and CCL5 [65, 66]. Thus,
NK cells may inhibit HIV replication by secreting CCL3,
CCL4, and CCL5 as well as other chemokines or soluble-
effector molecules.
http://www.jleukbio.org
PARTICIPATION OF CHEMOKINES IN NK
CELL RESPONSES TO INFECTION
AND CANCER
Elegant work has demonstrated the crucial role of chemokines
in the adaptive immune response and the biology of T and B
lymphocytes [22–26]. For example, antigen-specific T- and
B-cell responses are impaired severely in CCR7-deficient mice
[77]. This impairment does not appear to be caused by intrinsic
defects in mature T or B lymphocytes, but rather the failure of
T cells, B cells, and dendritic cells to migrate appropriately to
secondary lymphoid tissues [77]. In contrast, the effects of
deficiencies of specific chemokines or chemokine receptors on
NK cell development and function have not been described in
detail. Therefore, the role of chemokines in NK cell biology in
vivo must be inferred from indirect evidence.
An exception to this limitation is the clearly defined role of
CCL3 in NK cell-mediated protection from MCMV. NK cells
become activated in vivo early in the course of MCMV infec-
tion, and protective antiviral immune responses require IFN-␥
produced by NK cells [5]. Migration of NK cells into the liver
is necessary for successful clearance of MCMV infection [6,
55]. Expression of CCL3 mRNA and protein is induced in the
murine liver following MCMV infection, and migration of adop-
tively transferred NK cells to the liver of MCMV-infected mice
is abrogated by administration of neutralizing anti-CCL3 anti-
body [55]. Moreover, migration of NK cells to the liver, local
IFN-␥ production, and NK cell-dependent antiviral protection
are markedly diminished in CCL3-deficient mice infected with
MCMV [6, 55]. CCL3-deficient mice uniformly succumb to
MCMV infection, whereas wild-type mice control the infection
and survive. Serum IFN-␥ levels are the same in CCL3-
deficient and wild-type mice, indicating that local IFN-␥ pro-
duction in the liver is critical for control of MCMV infection.
Abundant production of CXCL9 occurred in the livers of
wild-type but not CCL3-deficient mice after MCMV infection
[6]. Depletion of NK cells strongly inhibited this CXCL9
production. Furthermore, CXCL9 production was not detected
in the livers of IFN-␥-deficient mice infected with MCMV.
Therefore, it is likely that local secretion of IFN-␥ in the liver
by activated NK cells is responsible for CXCL9 production
during MCMV infection. Furthermore, neutralization of CXCL9
in vivo was associated with a marked increase in MCMV titers
in the liver and a fatal outcome [6]. Thus, protective immune
responses to MCMV require expression of CCL3 in the liver to
attract activated NK cells, local IFN-␥ secretion by activated
NK cells, and subsequent production of CXCL9 in the liver.
Local production of CXCL9 and CXCL10 can also stimulate
NK cell-dependent protective responses to recombinant vac-
cinia viruses in vivo [78].
The cell types in the liver that produce CXCL9 during
MCMV infection have not been identified clearly, but hepato-
cytes can produce this chemokine [79]. Moreover, a fourfold
increase in liver NK cell numbers was observed in MCMV-
infected as compared with uninfected CCL3-deficient mice [6].
Although this degree of NK cell infiltration is apparently not
sufficient for ultimate control of MCMV, it suggests that factors
other than CCL3 can stimulate NK cell migration into the liver
in vivo.
Leishmania major is an obligate intracellular pathogen that
can cause cutaneous or disseminated disease. Resistant strains
of mice, such as C57BL/6, develop a Th1-dominated immune
response to this pathogen and recover from infection [4, 80,
81]. Conversely, susceptible strains, such as Balb/c, develop
Th2 responses and succumb to disseminated disease. It has
been shown that IFN-␥ produced by activated NK cells in
reactive lymph nodes promotes protective Th1 immune re-
sponses to L. major [4]. Moreover, parasite burden is correlated
inversely with the level of NK cell cytotoxicity present in
regional lymph nodes. Susceptibility of Balb/c mice appears to
be a result of, at least in part, defective NK cell activation at
the site of infection as a consequence of inadequate, local
IL-12 production by macrophages [80]. However, failure to
activate NK cells properly in draining lymph nodes could also
contribute to fatal leishmaniasis. Following infection with
Leishmania, lower NK cell cytotoxicity is observed in the
draining lymph nodes of susceptible Balb/c mice as compared
with resistant C57BL/6 mice [4, 82], although the number of
NK cells present does not differ between the two strains [82].
Message for XCL1, CCL2, and CXCL10 is expressed in drain-
ing lymph nodes from resistant but not susceptible mice during
the early phases of Leishmania infection [82]. Furthermore,
local injection of CXCL10 in vivo augmented NK cytotoxicity
in the draining lymph nodes of Balb/c mice infected with
Leishmania [82]. Thus, defective production CXCL10 and
other chemokines in regional lymph nodes, with subsequent,
inadequate stimulation of NK cell cytotoxicity and/or cytokine
production, may contribute to the susceptibility of Balb/c mice
to Leishmania infection.
In addition to their crucial role in the response to some
obligate intracellular pathogens, NK cells can contribute to the
rejection of malignant tumors. Preclinical animal models indi-
cate that chemokines participate in the NK cell response to
cancer. Systemic administration of IL-12 can induce the com-
plete regression of established tumors, inhibit the formation of
distant metastases, and prolong the survival of tumor-bearing
mice [83]. Depending on the experimental system used, CD4 T
cells, CD8 T cells, and NK cells have been found to contribute
to the antitumor activity of IL-12. Furthermore, production of
IFN-␥ in vivo is necessary but not sufficient for the antitumor
effects of IL-12 [84, 85]. IFN-␥ secreted by IL-12-activated T
and NK cells can in turn stimulate the production of several
cytokines including CXCL9 and CXCL10. The latter are re-
quired for tumor regression during IL-12 therapy [86]. The
antitumor effects of CXCL9 and CXCL10 are due to recruit-
ment of CXCR3-bearing antitumor-effector cells as well as the
inhibition of tumor angiogenesis [86 – 89]. Thus, CXCL9,
CXCL10, and possibly other chemokines can participate in NK
cell-mediated antitumor effects during cytokine-based immu-
notherapy for cancer.
Systemic administration of immunostimulatory cytokines
can be associated with substantial toxicity [90]. An alternative
approach for cancer immunotherapy is vaccination with cyto-
kine gene-transduced tumor cells. Injection of tumor cells
transduced with genes encoding one or more of several immu-
nostimulatory cytokines can stimulate the rejection of estab-
lished, nontransduced tumors and promote durable, specific
antitumor immunity [91, 92]. Antitumor effects have also been
Robertson Chemokine role in biology of NK cells 179
observed after vaccination with chemokine gene-transduced
tumor cells. Transduction of the C26 murine-colon adenocar-
cinoma cell line with a cDNA encoding CCL21 does not affect
the in vitro growth of the malignant cells but does reduce their
tumorigenicity in vivo [93]. Depletion of CD8 T cells or NK
cells in vivo led to more rapid growth of tumors, indicating that
both lymphocyte subsets participate in the response to CCL21-
transduced C26 cells. CCR7 and CXCR3 are receptors for
CCL21 in the mouse [39, 94]. Expression of CCR7 mRNA but
not CXCR3 mRNA was increased dramatically in tumors
formed by CCL21-transduced C26 cells as compared with
nontransduced cells [93]. These results suggest that paracrine
secretion of CCL21 by transduced C26 cells recruits CCR7-
expressing effector cells, which then inhibit tumor cell growth.
CCR7 is a receptor for CCL19 as well as CCL21. Transduc-
tion of the C3L5 murine-breast adenocarcinoma cell line with
a cDNA encoding CCL19 substantially reduces its tumorige-
nicity in vivo without affecting its in vitro growth [95]. NK cells
and to a lesser degree CD4 T cells contribute to the rejection
of CCL19-transduced C3L5 cells; CD8 T cells do not appear to
be involved. Vaccination with CCL19-transduced tumor cells
does not confer protection from subsequent rechallenge with
nontransduced C3L5 cells, although the latter grow more
slowly in vaccinated compared with nonvaccinated animals
[95]. In contrast to the initial rejection of CCL19-transduced
cells, partial immunity to rechallenge with nontransduced
C3L5 appears to be mediated entirely by CD4 T cells, without
participation of NK cells or CD8 T cells.
In preclinical models using the Meth A fibrosarcoma or
HM-1 ovarian carcinoma cell lines, injection with tumor cells
transduced with cDNA encoding CCL19, CCL21, or CXCL12
appeared to augment antitumor immune responses evoked by
vaccination with tumor cells expressing IL-2 or granulocyte-
macrophage colony-stimulating factor (GM-CSF) [96]. In
agreement with the C26 and C3L5 models [93, 95], vaccination
with chemokine-expressing tumor cells alone did not stimulate
durable, protective antitumor immunity [96].
Transduction of the CCL2 gene has also been demonstrated
to alter the tumorigenicity or immunogenicity of malignant
cells in several models [97–99]. Suppression of tumor forma-
tion [98] and metastasis [99] by CCL2-transduced cells in
T-cell-deficient nu/nu or SCID mice suggests a response by
innate immune effectors such as NK cells and monocytes.
Indeed, NK cells have been shown to mediate the inhibition of
metastasis by CCL2-transduced human lung adenocarcinoma
cells in the SCID mouse model [99].
CONCLUDING REMARKS
Chemokines have been shown to play a central role in the
migration and trafficking of T and B lymphocytes in vivo
[22–27]. It is likely that chemokines have a similar role in the
biology of NK cells. Differential expression of chemokine re-
ceptors [30] and adhesion molecules [30, 100, 101] by
CD56bright and CD56dim human NK cells suggests that these
subsets may home to different microenvironments in vivo [14].
Indeed, expression of CCR7 and high levels of L-selectin by
resting CD56bright NK cells [11, 30, 100] should direct them to
180 Journal of Leukocyte Biology Volume 71, February 2002
secondary lymphoid tissues [30, 41, 100 –103]. Because
CD56bright NK cells produce large quantities of IFN-␥ and
other cytokines after activation [11, 16, 62], it is also reason-
able to hypothesize that they can regulate adaptive T- and
B-cell responses in secondary lymphoid tissues. In contrast,
resting CD56dim NK cells do not express CCR7 and express
little or no L-selectin [11, 30, 100]; however, they express high
levels of LFA-1 and other adhesion molecules [17, 30, 40,
100]. Thus, CD56dim NK cells are expected to migrate to
peripheral nonlymphoid tissues rather than secondary lym-
phoid organs. However, CD56dim NK cells express CCR7 after
activation [40], which could promote their migration to regional
lymph nodes after they have been stimulated at sites of inflam-
mation in peripheral tissues. Chemokines can also affect the
cytolytic activity and proliferation of NK cells, potentially
indicating a major role for chemokines in the regulation of NK
cell responses to tumors and infectious pathogens. Further
investigation is required to dissect the contribution of chemo-
kines to the migration and effector function of NK cells in vivo.
Such studies will further our understanding of basic NK cell
biology and may facilitate the manipulation of NK cells in the
treatment of human infectious and neoplastic diseases.
ACKNOWLEDGMENTS
The author is supported in part by a National Institutes of
Health grant 3MO1 RR00750-27S3. I am grateful to Barrett
Rollins, M.D., Ph.D., Hal Broxmeyer, Ph.D., and Robert Hro-
mas, M.D., for providing helpful comments and suggestions.
REFERENCES
1. Robertson, M. J., Ritz, J. (1990) Biology and clinical relevance of human
natural killer cells. Blood 76, 2421–2438.
2. Timonen, T. (1997) Natural killer cells: endothelial interactions, migra-
tion, and target cell recognition. J. Leukoc. Biol. 62, 693–701.
3. Trinchieri, G. (1989) Biology of natural killer cells. Adv. Immunol. 47,
187–376.
4. Scharton, T. M., Scott, P. (1993) Natural killer cells are a source of
interferon ␥ that drives differentiation of CD4⫹ T cell subsets and
induces early resistance to Leishmania major in mice. J. Exp. Med. 178,
567–577.
5. Orange, J. S., Wang, B., Terhorst, C., Biron, C. A. (1995) Requirement
for natural killer cell-produced interferon ␥ in defense against murine
cytomegalovirus infection and enhancement of this defense pathway by
interleukin 12 administration. J. Exp. Med. 182, 1045–1056.
6. Salazar-Mather, T. P., Hamilton, T. A., Biron, C. A. (2000) A chemokine-
to-cytokine-to-chemokine cascade critical in antiviral defense. J. Clin.
Investig. 105, 985–993.
7. Abbas, A. K., Murphy, K. M., Sher, A. (1996) Functional diversity of
helper T lymphocytes. Nature 383, 787–793.
8. Gumperz, J. E., Parham, P. (1995) The enigma of the natural killer cell.
Nature 378, 245–248.
9. Lanier, L. L. (1997) Natural killer cells: from no receptors to too many.
Immunity 6, 371–378.
10. Moretta, A., Bottino, C., Vitale, M., Pende, D., Cantoni, C., Mingari,
M. C., Biassoni, R., Moretta, L. (2001) Activating receptors and core-
ceptors involved in human natural killler cell-mediated cytolysis. Annu.
Rev. Immunol. 19, 197–223.
11. Nagler, A., Lanier, L. L., Cwirla, S., Phillips, J. H. (1989) Comparative
studies of human FcR III-positive and negative natural killer cells.
J. Immunol. 143, 3183–3191.
12. Caligiuri, M. A., Zmuidzinas, A., Manley, T. J., Levine, H., Smith, K. A.,
Ritz, J. (1990) Functional consequences of interleukin 2 receptor ex-
pression on resting human lymphocytes: identification of a novel natural
http://www.jleukbio.org
 killer cell subset with high affinity receptors. J. Exp. Med. 171, 1509 –
1526.
13. Baume, D. M., Robertson, M. J., Levine, H., Manley, T. J., Schow, P. W.,
Ritz, J. (1992) Differential responses to interleukin-2 define functionally
distinct subsets of human natural killer cells. Eur. J. Immunol. 22, 1– 6.
14. Cooper, M. A., Fehniger, T. A., Caligiuri, M. A. (2001) The biology of
human natural killer cell subsets. Trends Immunol. 22, 633– 640.
15. Carson, W. E., Giri, J. G., Lindemann, M. J., Linett, M. L., Ahdieh, M.,
Paxton, R., Anderson, D., Eisenmann, J., Grabstein, K., Caligiuri, M. A.
(1994) Interleukin (IL) 15 is a novel cytokine that activates human
natural killer cells via components of the IL-2 receptor. J. Exp. Med. 180,
1395–1403.
16. Cooper, M. A., Fehniger, T. A., Turner, S. C., Chen, K. S., Ghaheri, B. A.,
Ghayur, T., Carson, W. E., Caligiuri, M. A. (2001) Human natural killer
cells: a unique immunoregulatory role for the CD56bright subset. Blood
97, 3146 –3151.
17. Robertson, M. J., Caligiuri, M. A., Manley, T. J., Levine, H., Ritz, J.
(1990) Human natural killer cell adhesion molecules: differential ex-
pression after activation and participation in cytolysis. J. Immunol. 145,
3194 –3201.
18. Robertson, M. J., Soiffer, R. J., Wolf, S. F., Manley, T. J., Donahue, C.,
Young, D., Herrmann, S. H., Ritz, J. (1992) Response of human natural
killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity
and proliferation of NK cells is differentially regulated by NKSF. J. Exp.
Med. 175, 779 –788.
19. Robertson, M. J., Cameron, C., Atkins, M. B., Gordon, M. S., Lotze, M. T.,
Sherman, M. L., Ritz, J. (1999) Immunologic effects of interleukin 12
administered by bolus intravenous injection to patients with cancer. Clin.
Cancer Res. 5, 9 –16.
20. Caligiuri, M. A., Murray, C., Robertson, M. J., Wang, E., Cochran, K.,
Cameron, C., Schow, P., Ross, M. E., Klumpp, T. R., Soiffer, R. J., Smith,
K., Ritz, J. (1993) Selective modulation of human natural killer cells in
vivo after prolonged infusion of low dose recombinant interleukin 2.
J. Clin. Investig. 91, 123–132.
21. Ellis, T. M., Creekmore, S. P., McMannis, J. D., Braun, D. P., Harris,
J. A., Fisher, R. I. (1988) Appearance and phenotypic characterization of
circulating Leu 19⫹ cells in cancer patients receiving recombinant
interleukin 2. Cancer Res. 48, 6597– 6602.
22. Rollins, B. J. (1997) Chemokines. Blood 90, 909 –928.
23. Rossi, D., Zlotnik, A. (2000) The biology of chemokines and their
receptors. Annu. Rev. Immunol. 18, 217–242.
24. Kim, C. H., Broxmeyer, H. E. (1999) Chemokines: signal lamps for
trafficking of T and B cells for development and effector function.
J. Leukoc. Biol. 65, 6 –15.
25. Berger, E. A., Murphy, P. M., Farber, J. M. (1999) Chemokine receptors
as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu.
Rev. Immunol. 17, 657–700.
26. Christopherson II, K., Hromas, R. (2001) Chemokine regulation of nor-
mal and pathologic immune responses. Stem Cells 19, 388 –396.
27. Yoshie, O., Imai, T., Nomiyama, H. (2001) Chemokines in immunity.
Adv. Immunol. 78, 57–110.
28. Rollins, B. J., ed. (1999) Chemokines and Cancer, Totowa, NJ, Humana.
29. Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R.,
Matsushima, K., Miller, L. H., Oppenheim, J. J., Power, C. A. (2000)
Nomenclature for chemokine receptors. Pharmacol. Rev. 52, 145–176.
30. Campbell, J. J., Qin, S., Unutmaz, D., Soler, D., Murphy, K. E., Hodge,
M. R., Wu, L., Butcher, E. C. (2001) Unique subpopulations of CD56⫹
NK and NK-T peripheral blood lymphocytes identified by chemokine
receptor expression. J. Immunol. 166, 6477– 6482.
31. Chuntharapai, A., Lee, J., Hebert, C. A., Kim, K. J. (1994) Monoclonal
antibodies detect different distribution patterns of IL-8 receptor A and
IL-8 receptor B on human peripheral blood lymphocytes. J. Immunol.
153, 5682–5688.
32. Morohashi, H., Miyawaki, T., Nomura, H., Kuno, K., Murakami, S.,
Matsushima, K., Mukaida, N. (1995) Expression of both types of human
interleukin-8 receptors on mature neutrophils, monocytes, and natural
killer cells. J. Leukoc. Biol. 57, 180 –187.
33. Yoneda, O., Imai, T., Goda, S., Inoue, H., Yamauchi, A., Okazaki, T.,
Imia, H., Yoshie, O., Bloom, E. T., Domae, N., Umehara, H. (2000)
Fractalkine-mediated endothelial cell damage by NK cells. J. Immunol.
164, 4055– 4062.
34. Imai, T., Hieshima, K., Haskell, C., Baba, M., Nagira, M., Nishimura, M.,
Kakizaki, M., Takagi, S., Nomiyama, H., Schall, T. J., Yoshie, O. (1997)
Identification and molecular characterization of fractalkine receptor
CX3CR1, which mediates both leukocyte migration and adhesion. Cell
91, 521–530.
35. Inngjerdingen, M., Damaj, B., Maghazachi, A. A. (2001) Expression and
regulation of chemokine receptors in human natural killer cells. Blood
97, 367–375.
36. Taub, D. D., Sayers, T. J., Carter, C. R. D., Ortaldo, J. R. (1995) ␣ and
␤ Chemokines induce NK cell migration and enhance NK-mediated
cytolysis. J. Immunol. 155, 3877–3888.
37. Nieto, M., Navarro, F., Perez-Villar, J. J., del Pozo, M. A., Gonzalez-
Amaro, R., Mellado, M., Frade, J. M. R., Martinez-A, C., Lopez-Botet,
M., Sanchez-Madrid, F. (1998) Role of chemokines and receptor polar-
ization in NK-target cell interactions. J. Immunol. 161, 3330 –3339.
38. Polentarutti, N., Allavena, P., Bianchi, G., Giardina, G., Basile, A.,
Sozzani, S., Montovani, A., Introna, M. (1997) IL-2-regulated expression
of monocyte chemotactic protein-1 receptor (CCR2) in human NK cells:
characterization of a predominant 3.4-kilobase transcript containing
CCR2B and CCR2A sequences. J. Immunol. 158, 2689 –2694.
39. Campbell, J. J., Bowman, E. P., Murphy, K., Youngman, K. R., Siani,
M. A., Thompson, D. A., Wu, L., Zlotnick, A., Butcher, E. C. (1998)
6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed
by high endothelium, is an agonist for the MIP-3␤ receptor CCR7. J. Cell
Biol. 141, 1053–1059.
40. Robertson, M. J., Williams, B. T., Christopherson II, K., Brahmi, Z.,
Hromas, R. (2000) Regulation of human natural killer cell migration and
proliferation by the exodus subfamily of CC chemokines. Cell. Immunol.
199, 8 –14.
41. Yoshida, R., Nagira, M., Imai, T., Baba, M., Tagaki, S., Tabira, Y., Akagi,
J., Nomiyama, H., Yoshie, O. (1998) EBI1-ligand chemokine (ELC)
attracts a broad spectrum of lymphocytes: activated T cells strongly
up-regulate CCR7 and efficiently migrate toward ELC. Int. Immunol. 10,
901–910.
42. Kim, C. H., Pelus, L. M., Appelbaum, E., Johanson, K., Anzai, N.,
Broxmeyer, H. E. (1999) CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and
CK␤-11/MIP-3␤/ELC, are chemoattractants for CD56(⫹)CD16(⫺) NK
cells and late stage lymphoid progenitors. Cell. Immunol. 193, 226 –235.
43. Handgetinger, R., Welte, B., Dopfer, R., Niethammer, D. (1994) Rapid
method for purification of CD56⫹ natural killer cells with preferential
enrichment of the CD56bright⫹ subset. J. Clin. Lab. Anal. 8, 443– 446.
44. Allavena, P., Bianchi, G., Zhou, D., van Damme, J., Jilek, P., Sozzani, S.,
Mantovani, A. (1994) Induction of natural killer cell migration by mono-
cyte chemotactic protein-1, -2, and -3. Eur. J. Immunol. 24, 3233–3236.
45. Maghazachi, A. A., Skalhegg, B. S., Rolstad, B., Al-Aoukaty, A. (1997)
Interferon-inducible protein-10 and lymphotactin induce the chemotaxis
and mobilization of intracellular calcium in natural killer cells through
pertussis toxin-sensitive and -insensitive heterotrimeric G-proteins.
FASEB J. 11, 765–774.
46. Sebok, K., Woodside, D., Al-Aoukaty, A., Ho, A. D., Gluck, S., Maghaza-
chi, A. A. (1993) IL-8 induces the locomotion of human IL-2-activated
natural killer cells: involvement of a guanine binding (G0) protein. J.
Immunol. 150, 1524 –1534.
47. Loetscher, P., Seitz, M., Clark-Lewis, I., Bagglioni, M., Moser, B. (1996)
Activation of NK cells by CC chemokines: chemotaxis, Ca2⫹ mobiliza-
tion, and enzyme release. J. Immunol. 156, 322–327.
48. Al-Aoukaty, A., Schall, T. J., Maghazachi, A. (1996) Differential cou-
pling of CC chemokine receptors to multiple heterotrimeric G proteins in
human interleukin-2-activated natural killer cells. Blood 87, 4255–
4260.
49. Romagnani, P., Annunziato, F., Lazzeri, E., Cosmi, L., Beltrame, C.,
Lasagni, L., Galli, G., Francalanci, M., Manetti, R., Marra, F., Vanini, V.,
Maggi, E., Romagnani, S. (2001) Interferon-inducible protein 10, mono-
kine induced by interferon gamma, and interferon-inducible T-cell alpha
chemoattractant are produced by thymic epithelial cells and attract
T-cell receptor (TCR) ␣␤⫹ CD8⫹ single-positive T cells, TCR ␥␦⫹ T
cells, and natural killer-type cells in human thymus. Blood 97, 601– 607.
50. Bianchi, G., Sozzani, S., Zlotnick, A., Mantovani, A., Allavena, P. (1996)
Migratory response of human natural killer cells to lymphotactin. Eur.
J. Immunol. 26, 3238 –3241.
51. Drake, P. M., Gunn, M. D., Charo, I. F., Tsou, C-L., Zhou, Y., Huang, L.,
Fisher, S. J. (2001) Human placental cytotrophoblasts attract monocytes
and CD56bright natural killer cells via the actions of monocyte inflam-
matory protein 1␣. J. Exp. Med. 193, 1199 –1212.
52. Inngjerdingen, M., Damaj, B., Maghazachi, A. A. (2000) Human NK cells
express CC chemokine receptors 4 and 8 and respond to thymus and
activation-regulated chemokine, macrophage-derived chemokine, and
I-309. J. Immunol. 164, 4048 – 4054.
53. Godiska, R., Chantry, D., Raport, C. J., Sozzani, S., Allavena, P., Leviten,
D., Mantovani, A., Gray, P. W. (1997) Human macrophage-derived
chemokine (MDC), a novel chemoattractant for monocytes, monocyte-
derived dendritic cells, and natural killer cells. J. Exp. Med. 185,
1595–1604.
Robertson Chemokine role in biology of NK cells 181
54. Hedrick, J. A., Saylor, V., Figueroa, D., Mizoue, L., Xu, Y., Menon, S.,
Abrams, J., Handel, T., Zlotnick, A. (1997) Lymphotactin is produced by
NK cells and attracts both NK cells and T cells in vivo. J. Immunol. 158,
1533–1540.
55. Salazar-Mather, T. P., Orange, J. S., Biron, C. A. (1998) Early murine
cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell
inflammation and protection through macrophage inflammatory protein
1␣ (MIP-1␣)-dependent pathways. J. Exp. Med. 187, 1–14.
56. Grimm, E. A., Mazumder, A., Zhang, H. Z., Rosenberg, S. A. (1982)
Lymphokine-activated killer cell phenomenon: lysis of natural killer-
resistant fresh solid tumor cells by interleukin 2-activated autologous
human peripheral blood lymphocytes. J. Exp. Med. 155, 1823–1841.
57. Taub, D. D., Ortaldo, J. R., Turcoviski-Corrales, S. M., Key, M. L.,
Longo, D. L., Murphy, W. J. (1996) ␤ Chemokines costimulate lympho-
cyte cytolysis, proliferation, and cytokine production. J. Leukoc. Biol. 59,
81– 89.
58. Maghazachi, A., Al-Aoukaty, A., Schall, T. J. (1996) CC chemokines
induce the generation of killer cells from CD56⫹ cells. Eur. J. Immunol.
26, 315–319.
59. Doherty, P. C. (1993) Cell-mediated cytotoxicity. Cell 75, 607– 612.
60. Robertson, M. J., Manley, T. J., Donahue, C., Levine, H., Ritz, J. (1993)
Costimulatory signals are required for optimal proliferation of human
natural killer cells. J. Immunol. 150, 1705–1714.
61. Robertson, M. J., Cameron, C., Lazo, S., Cochran, K. J., Voss, S. D., Ritz,
J. (1997) Costimulation of human natural killer cell proliferation: role of
accessory cytokines and cell contact-dependent signals. Nat. Immunol.
15, 213–226.
62. Voss, S. D., Daley, J., Ritz, J., Robertson, M. J. (1998) Participation of
the CD94 receptor complex in costimulation of human natural killer
cells. J. Immunol. 160, 1618 –1626.
63. Nandi, D., Gross, J. A., Allison, J. P. (1994) CD28-mediated costimula-
tion is necessary for optimal proliferation of murine NK cells. J. Immu-
nol. 152, 3361–3369.
64. Rabinowich, H., Sedlmayr, P., Herberman, R. B., Whiteside, T. L. (1991)
Increased proliferation, lytic activity, and purity of human natural killer
cells cocultured with mitogen-activated feeder cells. Cell. Immunol. 135,
454 – 470.
65. Fehniger, T. A., Herbein, G., Yu, H., Para, M. I., Bernstein, Z. P.,
O’Brien, W. A., Caligiuri, M. A. (1998) Natural killer cells from HIV-1⫹
patients produce C–C chemokines and inhibit HIV-1 infection. J. Im-
munol. 161, 6433– 6438.
66. Oliva, A., Kinter, A. L., Vaccarezza, M., Rubbert, A., Catanzaro, A.,
Moir, S., Monaco, J., Ehler, L., Mizell, S., Jackson, R., Li, Y., Romano,
J. W., Fauci, A. S. (1998) Natural killer cells from human immunodefi-
ciency virus (HIV)-infected individuals are an important source of CC-
chemokines and suppress HIV-1 entry and replication in vitro. J. Clin.
Investig. 102, 223–231.
67. Andrew, D. P., Chang, M. S., McNinch, J., Wathen, S. T., Rihanek, M.,
Tseng, J., Spellberg, J. P., Elias III, C. G. (1998) STCP-1 (MDC) CC
chemokine acts specifically on chronically activated Th2 lymphocytes
and is produced by monocytes on stimulation with Th2 cytokines IL-4
and IL-13. J. Immunol. 161, 5027–5038.
68. Fehniger, T. A., Shah, M. H., Turner, M. J., VanDeusen, J. B., Whitman,
S. P., Cooper, M. A., Suzuki, K., Wechser, M., Goodsaid, F., Caligiuri,
M. A. (1999) Differential cytokine and chemokine gene expression by
human NK cells following activation with IL-18 or IL-15 in combination
with IL-12: implications for the innate immune response. J. Immunol.
162, 4511– 4520.
69. Bluman, E. M., Bartynski, K. J., Avalos, B. R., Caligiuri, M. A. (1996)
Human natural killer cells produce abundant macrophage inflammatory
protein-1␣ in response to monocyte-derived cytokines. J. Clin. Investig.
97, 2722–2727.
70. Henneman, B., Tam, Y. K., Tonn, T., Klingemann, H-G. (1999) Expres-
sion of SCM-1␣/lymphotactin and SCM-1␤ in natural killer cells is
upregulated by IL-2 and IL-12. DNA Cell Biol. 18, 565–571.
71. Saito, S., Kasahara, T., Sakakura, S., Enomoto, M., Umekage, H.,
Harada, N., Morii, T., Nishikawa, K., Narita, N., Ichijo, M. (1994)
Interleukin-8 production by CD16⫺ CD56bright natural killer cells in the
human early pregnancy decidua. Biochem. Biophys. Res. Comm. 200,
378 –383.
72. Kubin, M., Cassiano, L., Chalupny, J., Chin, W., Cosman, D., Fanslow,
W., Mullberg, J., Rousseau, A-M., Ulrich, D., Armitage, R. (2001)
ULBP1, 2, 3: novel MHC class I-related molecules that bind to human
cytomegalovirus glycoprotein UL16, activate NK cells. Eur. J. Immunol.
31, 1428 –1437.
73. Ortaldo, J. J., Bere, E. W., Hodge, D., Young, H. A. (2001) Activating
Ly-49 NK receptors: central role in cytokine and chemokine production.
J. Immunol. 166, 4994 – 4999.
182 Journal of Leukocyte Biology Volume 71, February 2002
74. Cosman, D., Mullberg, J., Sutherland, C. L., Chin, W., Armitage, R.,
Fanslow, W., Kubin, M., Chalupny, N. J. (2001) ULBPs, novel MHC
class I-related molecules, bind to CMV glycoprotein UL16 and stimulate
NK cytotoxicity through NKG2D receptor. Immunity 14, 123–133.
75. Mainiero, F., Soriani, A., Stippoli, R., Jacobelli, J., Gismondi, A., Piccoli,
M., Frati, L., Santoni, A. (2000) RAC1/p38 MAPK signaling pathway
controls ␤1 integrin-induced interleukin-8 production in human natural
killer cells. Immunity 12, 7–16.
76. Somersalo, K., Carpen, O., Saksela, E. (1994) Stimulated natural killer
cells secrete factors with chemotactic activity, including NAP-1/IL-8,
which supports VLA-4- and VLA-5-mediated migration of T lympho-
cytes. Eur. J. Immunol. 24, 2957–2965.
77. Forster, R., Schubel, A., Breitfeld, D., Kremmer, E., Renner-Muller, I.,
Wolf, E., Lipp, M. (1999) CCR7 coordinates the primary immune re-
sponse by establishing functional microenvironments in secondary lym-
phoid organs. Cell 99, 23–33.
78. Mahalingam, S., Farber, J. M., Karupiah, G. (1999) The interferon-
inducible chemokines MuMig and Crg-2 exhibit antiviral activity in vivo.
J. Virol. 73, 1479 –1491.
79. Park, J-W., Gruys, M. E., McCormick, K., Lee, J-K., Subleski, J.,
Wigginton, J. M., Fenton, R. G., Wang, J-M., Wiltrout, R. H. (2001)
Primary hepatocytes from mice treated with IL-2/IL-12 produce T cell
chemoattractant activity that is dependent on monokine induced by
IFN-␥ (Mig) and chemokine responsive to ␥-2 (Crg-2). J. Immunol. 166,
3763–3770.
80. Reiner, S. L., Zheng, S., Wang, Z-E., Stowring, L., Locksley, R. M.
(1994) Leishmania promastigotes evade interleukin 12 (IL-12) induction
by macrophages and stimulate a broad range of cytokines from CD4⫹ T
cells during initiation of infection. J. Exp. Med. 179, 447– 456.
81. Scharton-Kersten, T., Afonso, L. C. C., Wysocka, M., Trinchieri, G.,
Scott, P. (1995) IL-12 is required for natural killer cell activation and
subsequent T helper 1 development in experimental Leishmaniasis.
J. Immunol. 154, 5320 –5330.
82. Vester, B., Muller, K., Solbach, W., Laskay, T. (1999) Early gene
expression of NK cell-activating chemokines in mice resistant to Leish-
mania major. Infect. Immun. 67, 3155–3159.
83. Robertson, M. J., Ritz, J. (1996) Interleukin 12: basic biology and
potential applications in cancer treatment. The Oncologist 1, 93–102.
84. Nastala, C. L., Edington, H. D., McKinney, T. G., Tahara, H., Nalesnik,
M. A., Brunda, M. J., Gately, M. K., Wolf, S. F., Schreiber, R. D.,
Storkus, W. J., Lotze, M. T. (1994) Recombinant IL-12 administration
induces tumor regression in association with IFN-␥ production. J. Im-
munol. 153, 1697–1706.
85. Brunda, M. J., Luistro, L., Hendrzak, J. A., Fountoulakis, M., Garotta, G.,
Gately, M. K. (1995) Role of interferon-␥ in mediating the antitumor
efficacy of interleukin-12. J. Immunother. 17, 71–77.
86. Tannenbaum, C. S., Tubbs, R., Armstrong, D., Finke, J., Bukowski,
R. M., Hamilton, T. A. (1998) The CXC chemokines IP-10 and Mig are
necessary for IL-12-mediated regression of the mouse RENCA tumor.
J. Immunol. 161, 927–932.
87. Coughlin, C. M., Salhany, K. E., Gee, M. S., LaTemple, D. C., Kotenko,
S., Ma, X., Gri, G., Wysocka, M., Kim, J. E., Liu, L., Laio, F., Farber,
J. M., Pestka, S., Trinchieri, G., Lee, W. M. F. (1998) Tumor cell
responses to IFN-␥ affect tumorigenicity and response to IL-12 therapy
and antiangiogenesis. Immunity 9, 25–34.
88. Sgadari, C., Angiolillo, A. L., Tosato, G. (1996) Inhibition of angiogenesis
by interleukin-12 is mediated by interferon-inducible protein 10. Blood
87, 3877–3882.
89. Yao, L., Sgadari, C., Furuke, K., Bloom, E. T., Teruya-Feldstein, J.,
Tosato, G. (1999) Contribution of natural killer cells to inhibition of
angiogenesis by interleukin-12. Blood 93, 1612–1621.
90. Siegel, J. P., Puri, R. K. (1991) Interleukin-2 toxicity. J. Clin. Oncol. 9,
694 –704.
91. Cornetta, K. G., Robertson, M. J. (2000) Basic principles of gene therapy:
basic principles and safety considerations. In Principles and Practice of
the Biologic Therapy of Cancer (S. A. Rosenberg, ed.), Philadelphia,
Lippincott, Williams and Wilkins, 733–747.
92. Vieweg, J., Gilboa, E. (1995) Considerations for the use of cytokine-
secreting tumor cell preparations for cancer treatment. Cancer Investig.
13, 193–201.
93. Vicari, A. P., Ait-Yahia, S., Chemin, K., Mueller, A., Zlotnik, A., Caux,
C. (2000) Antitumor effects of the mouse chemokine 6Ckine/SLC through
angiostatic and immunological mechanisms. J. Immunol. 165, 1992–
2000.
94. Soto, H., Wang, W., Strieter, R. M., Copeland, N. G., Gilbert, D. J.,
Jenkins, N. A., Hedrick, J., Zlotnick, A. (1998) The CC chemokine
6Ckine binds the CXC chemokine receptor CXCR3. Proc. Natl. Acad.
Sci. USA 95, 8205– 8210.
http://www.jleukbio.org
 95. Braun, S. E., Chen, K., Foster, R. G., Orchard, P. J., Kim, C. H., Hromas, R.,
Kaplan, M. H., Broxmeyer, H. E., Cornetta, K. (2000) The CC chemokine
CK␤-11/MIP-3␤/ELC/Exodus 3 mediates tumor rejection of murine
breast cancer cells through NK cells. J. Immunol. 164, 4025– 4031.
96. Nomura, T., Hasegawa, H., Kohno, M., Sasaki, M., Fujita, S. (2001)
Enhancement of anti-tumor immunity by tumor cells transfected with the
secondary lymphoid tissue chemokine, EBI-1-ligand chemokine and
stromal cell-derived factor-1␣ chemokine genes. Int. J. Cancer 91,
597– 606.
97. Manome, Y., Wen, P. Y., Hershowitz, A., Tanaka, T., Rollins, B. J., Kufe,
D. W., Fine, H. A. (1995) Monocyte chemoattractant protein-1 (MCP-1)
gene transduction: an effective tumor vaccine strategy for non-intracra-
nial tumors. Cancer Immunol. Immunother. 41, 227–235.
98. Rollins, B. J., Sunday, M. E. (1991) Suppression of tumor formation in
vivo by expression of the JE gene in malignant cells. Mol. Cell. Biol. 11,
3125–3131.
99. Nokihara, H., Yanagawa, H., Nishioka, Y., Yano, S., Mukaida, N.,
Matsushima, K., Sone, S. (2000) Natural killer cell-dependent suppres-
sion of systemic spread of human lung adenocarcinoma cells by mono-
cyte chemoattractant protein-1 gene transfection in severe combined
immunodeficient mice. Cancer Res. 60, 7002–7007.
100. Frey, M., Packianathan, N. B., Fehniger, T. A., Ross, M. E., Wang, W-C.,
Stewart, C. C., Caligiuri, M. A., Evans, S. S. (1998) Differential expres-
sion and function of L-selectin on CD56bright and CD56dim NK cell
subsets. J. Immunol. 161, 400 – 408.
101. Andre, P., Spertini, O., Guia, S., Rihet, P., Dignat-George, F., Brailly, H.,
Sampol, J., Anderson, P. J., Vivier, E. (2000) Modification of P-selectin
glycoprotein ligand-1 with a natural killer cell-restricted sulfated lac-
tosamine creates an alternate ligand for L-selectin. Proc. Natl. Acad. Sci.
USA 97, 3400 –3405.
102. Gunn, M. D., Tangemann, K., Tam, C., Cyster, J. G., Rosen, S. D.,
Williams, L. T. (1998) A chemokine expressed in lymphoid high endo-
thelial venules promotes the adhesion and chemotaxis of naive T lym-
phocytes. Proc. Natl. Acad. Sci. USA 95, 258 –263.
103. Rossi, D. L., Vicari, A. P., Franz-Bacon, K., McClanahan, T. K., Zlot-
nick, A. (1997) Identification through bioinformatics of two new macro-
phage proinflammatory human chemokines: MIP-3␣ and MIP-3␤. J. Im-
munol. 158, 1033–1036.
104. Qin, S., Rottman, J. B., Myers, P., Kassam, N., Weinblatt, M., Loetscher,
M., Koch, A. E., Moser, B., Mackay, C. R. (1998) The chemokine
receptors CXCR3 and CCR5 mark subsets of T cells associated with
certain inflammatory reactions. J. Clin. Investig. 101, 746 –753.
105. Maghazachi, A. A., Al-Aoukaty, A., Schall, T. J. (1994) C–C chemokines
induce the chemotaxis of NK and IL-2-activated NK cells. J. Immunol.
153, 4969 – 4977.
106. Robertson, M. J., Cochran, K. J., Cameron, C., Le, J-M., Tantravahi, R.,
Ritz, J. (1996) Characterization of a cell line, NKL, derived from an
aggressive human natural killer cell leukemia. Exp. Hematol. 24, 406 –
415.
Robertson Chemokine role in biology of NK cells 183