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Cutting Edge |
* Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria, Australia; and
Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Rae-1 expression on class I-deficient RMA-S lymphoma cells enhanced
primary NK cell-mediated tumor rejection in vivo, whereas RMA-Rae-1
tumor cells were rejected by a combination of NK cells and
CD8+ T cells. Rae-1 expression stimulated NK cell
cytotoxicity and IFN-
secretion in vitro, but not proliferation.
Surprisingly, only NK cell perforin-mediated cytotoxicity, but not
production of IFN-, was critical for the rejection of
Rae-1-expressing tumor cells in vivo. This distinct requirement for
perforin activity contrasts with the NK cell-mediated rejection of MHC
class I-deficient RMA-S tumor cells expressing other activating ligands
such as CD70 and CD80. Thus, these results indicated that NKG2D acted
as a natural cytotoxicity receptor to stimulate perforin-mediated
elimination of ligand-expressing tumor cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Of particular interest is the lectin-like NKG2D receptor expressed on
NK cells, TCR
+ T cells,
CD8+TCR
+ T cells, and
activated macrophages. NKG2D is associated with the transmembrane
adapter protein DAP10 and the cytoplasmic domain of DAP10 contains a
YxxM motif, which binds to the p85 subunit of the phosphatidylinositol
3-kinase and activates this kinase (17). Several ligands,
which bind to NKG2D, are structurally related to MHC class I molecules
(8, 10, 12). In humans, the polymorphic MHC class I
chain-related molecules
(MIC)3A and MICB can
be recognized by NKG2D (9, 18). Unlike conventional MHC
class I, those MIC proteins display up-regulated surface expression on
stressed cells and are frequently overexpressed by tumors
(19). Although MIC molecules have not been found in mice,
the retinoic acid early inducible-1 (Rae-1) gene products and a
distantly related minor histocompatibility Ag, H60, have been reported
as NKG2D ligands in mice (10, 12). Recent studies show
that the ectopic expression of NKG2D ligands in several tumor cell
lines resulted in the rejection of the tumor cells, even when the tumor
cells expressed normal levels of MHC class I molecules (20, 21).
NK cell rejection of tumors generally involves perforin (pfp)-mediated
cytotoxicity and the action of secreted IFN- (22, 23, 24, 25).
In this study, we have investigated the primary antitumor effector
mechanisms elicited by TAP-deficient RMA-S and parental RMA lymphomas
expressing Rae-1. Although Rae-1 ligation of NKG2D in vitro
triggered NK cell pfp-mediated cytotoxicity and IFN- secretion,
primary rejection of Rae-1 expressing RMA-S cells was mediated by NK
cells and pfp played a dominant role in this process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Inbred wild-type (WT) C57BL/6 mice were purchased
from the Walter and Eliza Hall Institute of Medical Research
(Melbourne, Australia). The following gene-targeted mice were bred at
the Peter MacCallum Cancer Institute (East Melbourne, Victoria,
Australia): C57BL/6 IFN--deficient
(IFN--/-) mice, C57BL/6 pfp-deficient
(pfp-/-) mice, and C57BL/6 RAG-1-deficient
(RAG-1-/-) mice. C57BL/6 mice doubly deficient
for pfp and IFN-
(pfp-/-IFN--/-) or
pfp and RAG-1
(RAG-1-/-pfp-/-) were
produced and bred at the Peter MacCallum Cancer Institute. Mice that
were 6–12 wk of age were used in all experiments that were performed
according to animal experimental ethics committee guidelines.
Abs and reagents
Purified mAbs reactive with mouse CD16/32 (2.4G2), mouse NK1.1
(PK136), mouse CD8 (53-6.7), and mouse IFN- (R4-6A2) were all
purified from hybridomas. Isotype control for rat IgG1 (R3-34), rat
IgG2a (R35-95) (BD PharMingen, San Diego, CA), and PE-labeled goat
anti-rat IgG (Caltag Laboratories, Burlingame, CA) were purchased.
Rabbit anti-asialo-GM1 (AGM1) Ab was purchased from WAKO (Richmond,
VA). Human IL-2 was kindly provided by Chiron (Emeryville,
CA).
Tumor cell lines
The RMA and RMA-S cell lines used in this study were derived
from C57BL/6 (B6, H-2b) mice. RMA and RMA-S are T
cell lymphomas derived from the Rauscher murine leukemia virus-induced
RBL-5 cell line (26). RMA-S and infectants were grown in
complete RPMI 1640 medium as previously described (27).
RMA-S-m (mock vector alone transfected), RMA-S-CD70, and RMA-S-Rae-1
infectants were prepared and selected by flow cytometry as previously
described (27). RMA and RMA-Rae-1 tumor cells were
prepared as described elsewhere (20) and analyzed by flow
cytometry using PE-labeled mNKG2D tetramer as described previously
(10).
NK cell culture and assay in vitro
Spleen NK cells from RAG-1-/- or
RAG-1-/-pfp-/- mice
were prepared and characterized as described elsewhere
(27). In coculture experiments, purified NK cells (3
x 105/well) were cocultured with irradiated
(15,000 rad) RMA-S-mock, RMA-S-Rae-1 cells, or RMA-S-CD70 at
indicated a responder:stimulator ratio in 96-well round-bottom culture
plate. For the proliferation assay, the NK cell cultures were incubated
for 2 days in the presence of IL-2 (25 U/ml). Cell-free supernatants
from NK cultures were harvested after 24-h incubation and subjected to
IFN- ELISA with a specific ELISA kit (BD PharMingen). Cytotoxic
activity of NK cells was assessed as described previously
(27). The anti-IFN- mAb (10 µg/ml) was added to
the cultures for blocking IFN-. Each experiment was performed three
times using triplicate samples.
Tumor growth assays
Groups of 5–10 untreated (WT, RAG-1-/-,
IFN--/-, pfp-/-,
pfp-/-IFN--/-) or
Ab-treated WT (anti-AGM1, anti-NK1.1, anti-CD8) mice were
injected s.c. with vector alone-infected- or Rae-1-infected tumor
cells (range, 5 x 104–5 x
106 cells) in 0.2 ml of PBS as indicated. Mice
were observed every 2 days for tumor growth using a caliper square
measuring along the perpendicular axes of the tumors (the product of
two diameters ± SE) and sacrificed when tumors reached a size
>12 mm in diameter. Mice without any signs of tumor growth were kept
under observation for at least 100 days. In some experiments in vivo,
to deplete NK cells, mice were treated on days -1, 0, and 7 (where day
0 is the day of primary tumor inoculation) with anti-AGM1 (200 µg
i.p) or anti-NK1.1 mAb (200 µg i.p.) as described elsewhere
(27). Alternatively, some groups of mice were treated as
described above with anti-CD8 mAb (200 µg i.p) to deplete
CD8+ cells or 200 µg of control Ig.
Statistical analysis
Data were analyzed using the Mann-Whitney U test. All p < 0.05 were considered to be significant.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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RMA-S, a MHC class I-deficient variant of RBL-5, is one of the
prototypic NK cell-sensitive target cells for in vitro and in vivo
studies (22, 23, 26). To examine the role of NKG2D in NK
cell-mediated tumor rejection, we prepared by retroviral infection,
RMA-S cells that expressed the vector alone (-mock) or the NKG2D
ligand Rae-1 (Fig. 1
). The control and
Rae-1-expressing cell lines had similar growth kinetics in vitro
(data not shown). Tumor cells that have lost MHC class I expression,
such as RMA-S, are efficiently controlled in vivo by NK cells
(26). Over a considerable dose range (5 x
104–5 x 106 cells),
RMA-S-Rae-1 tumor cells were rejected more avidly than RMA-S-mock
tumor cells (Fig. 2, A–F).
Tumor rejection was mediated entirely by NK cells in both cases as
evidenced by the increased tumor take and growth rate in WT or
RAG-1-/- mice treated with anti-AGM1 Ab
(Fig. 2, G and H). These data indicated that
Rae-1 expression could enhance primary NK cell-mediated tumor
rejection independently of T, NKT, or B cells.
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secretion, but not proliferation
We next examined whether Rae-1 expression on RMA-S
cells could induce cytotoxicity (Fig. 3A), proliferation (Fig. 3D), and IFN- production (Fig. 3E) by freshly
isolated naive NK cells in vitro. Rae-1 expression on RMA-S cells
triggered target cell killing by NK cells (Fig. 3A) without
prior activation and it was totally mediated by the pfp pathway (Fig. 3B). Although increased IFN- production of NK cells was
observed following interaction with RMA-S-Rae-1 (Fig. 3E), IFN- did not contribute to Rae-1-triggered
cytotoxicity (Fig. 3C). Interestingly, Rae-1 did not
induce NK cell proliferation, whereas it enhanced other defined NK cell
functions, such as cytotoxicity and IFN- production (Fig. 3D). By comparison, CD70 expression on RMA-S tumor cells has
been demonstrated to enhance NK cell-mediated proliferation and IFN-
secretion, but not cytotoxicity (Fig. 3, A, D,
and E and Ref. 27). Therefore, RMA-S-Rae-1
cells induce both cytotoxicity and IFN- production by NK cells in
vitro.
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Finally, we investigated the relative contribution of effector
molecules in the rejection of Rae-1-expressing primary tumors by NK
cells in vivo. Fig. 4A shows
that NK cell-mediated rejection of s.c. RMA-S tumor cells was pfp and
IFN- dependent as previously observed (27). As
previously demonstrated, CD70-expressing RMA-S cells were rejected
through both pfp- and IFN- dependent mechanisms (Fig. 4B and Ref. 27). Interestingly, NK
cell-mediated rejection of RMA-S-Rae-1 tumors occurred in WT (Fig. 4, C and G) and
IFN--/- (Fig. 4, E and
I) mice, but was not observed in either
pfp-/- mice (Fig. 4, D and
H) or
pfp-/-IFN--/- mice
(Fig. 4, F and J). Similar results were obtained
at a higher dose of RMA-S-Rae-1 tumor cells
(106) where 7 of 10 WT mice and 4 of 5
IFN--/- mice had developed tumors by day
20 (data not shown). These results indicated a critical requirement
for pfp-mediated cytotoxicity in NK cell rejection of
Rae-1-expressing tumors, whereas increased IFN- production of NK
cells (observed in vitro (Fig. 2
E)) played little role in
tumor rejection in vivo. We also observed that MHC class I-positive
RMA-Rae-1 tumors cells were rejected by either NK cells or
CD8+ T cells at low tumor doses (data not shown
and as previously described in Ref. 20). Again, rejection
occurred in WT and IFN--/- mice, but was not
observed in pfp-/- or
pfp-/-IFN--/- mice
(data not shown). These observations were also made in NK cell-depleted
or CD8+ cell-depleted mice, but not in NK and
CD8+ cell-depleted mice. This confirmed the
finding that CD8+ T cells participate in the
rejection of RMA-Rae-1 tumor cells (20), in contrast to
another report that only NK cells mediate rejection of RMA cells
transduced with Rae-1 (21). In addition, NKG2D-mediated
tumor rejection by both NK cells and CD8+ T cells
was pfp dependent, suggesting that in these lymphocytes NKG2D acts
predominantly as a natural cytotoxicity receptor.
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Although several NK cell receptors have been implicated in NK cell
cytolysis and tumor rejection, NKG2D was proposed to play an important
role in tumor immune surveillance (8, 28) since the
defined ligands are frequently overexpressed on many different tumor
cells (10, 19). Our results indicated that NKG2D
ligand-expressing tumor cells rapidly induced NK cell cytotoxicity in
vitro without any prior stimulation and rejected tumors through a
pfp-dependent mechanism in vivo. Surprisingly, IFN- production was
not critical for NKG2D ligand-expressing tumor cell rejection despite
its clear requirement in tumor rejection and the development of T cell
memory induced by other NK cell-activating molecules, such as CD27 and
CD28 (27, 29). It remains possible, but untested, that
NKG2D fails to stimulate NK cell IFN- production in vivo.
Alternatively, CD27 does not induce NK cell cytotoxicity, and enhanced
tumor rejection triggered via CD27 or CD28 might require additional
IFN--dependent signals from the tumor or dendritic cells. Therefore,
NKG2D may serve as a primary recognition receptor to allow elimination
of "dangerous" cells, such as transformed cancer cells, stressed,
or virus-infected cells, via direct pfp-mediated cytotoxicity. In
particular, this would be a more rapid and powerful stimulus designed
to specifically kill stressed or infected tissue cells that do not
typically express ligands for other immune-activating molecules such as
CD27 (CD70) and CD28 (CD80/86).
Whether or not NKG2D ligands play a critical role in immune detection
of spontaneous tumor formation is as yet untested. It was suggested
that NKG2D-stress ligand pathway played an important role in the
regulation of carcinogen-induced cutaneous malignancy by
+ T cells (30); however,
12-O-tetradecanoylphorbol-13-acetate plus
7,12-dimethylbenz(a)anthracene induction of skin papillomas
was clearly pfp independent (31). Therefore, NKG2D
recognition is not involved or another key effector pathway is
triggered in + T cells by NKG2D ligation.
Macrophages can express NKG2D (10), but not pfp, and hence
this receptor must regulate other important effector functions in vivo.
Perhaps it is surprising that isolated human and rodent tumors do often
express NKG2D ligands, given the powerful immunoselection pressure of
pfp (32) and the potential importance of the NKG2D-stress
ligand pathway in vivo (20, 21). Viruses that are
sensitive to pfp and infect dendritic cells (CMV) have evolved very
sophisticated means to avoid triggering the NKG2D-stress ligand pathway
(33) and therefore tumor cells that express NKG2D ligands
must evade elimination by either providing balancing inhibitory signals
to immune effector cells or developing pfp resistance. Resistance to
pfp may be a very important tumor escape mechanism to consider for
future study, since should NK cells select tumor cells that are pfp
resistant, adaptive immune responses using this pathway (e.g., CTL)
might also be quite ineffectual. Future studies that define the unique
features of NKG2D activation and elucidate the importance of other
effector molecules and chemokines downstream will be of great
interest.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mark J. Smyth, Cancer Immunology Program, Peter MacCallum Cancer Institute, Locked Bag 1, A’Beckett Street, 8006, Victoria, Australia. E-mail address: m.smyth{at}pmci.unimelb.edu.au
3 Abbreviations used in this paper: MIC, MHC class I chain-related molecule; AGM1, asialo-GM1; pfp, perforin; Rae-1, retinoic acid early inducible-1; WT, wild type.
Received for publication August 12, 2002. Accepted for publication September 19, 2002.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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T cells of MICA and MICB. Proc. Natl. Acad. Sci. USA 96:6879. activities independently control tumor initiation, growth, and metastasis. Blood 97:192. in primary and secondary immunity generated by NK cell-sensitive tumor-expressing CD80 in vivo. J. Immunol. 168:4472. T cells. Science 294:605.This article has been cited by other articles:
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C. Adam, S. King, T. Allgeier, H. Braumuller, C. Luking, J. Mysliwietz, A. Kriegeskorte, D. H. Busch, M. Rocken, and R. Mocikat DC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction Blood, July 1, 2005; 106(1): 338 - 344. [Abstract] [Full Text] [PDF]
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M. J. Smyth, M. E. Wallace, S. L. Nutt, H. Yagita, D. I. Godfrey, and Y. Hayakawa Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer J. Exp. Med., June 20, 2005; 201(12): 1973 - 1985. [Abstract] [Full Text] [PDF]
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N. D. Huntington, Y. Xu, S. L. Nutt, and D. M. Tarlinton A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells J. Exp. Med., May 2, 2005; 201(9): 1421 - 1433. [Abstract] [Full Text] [PDF]
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A. Bielawska-Pohl, C. Crola, A. Caignard, C. Gaudin, D. Dus, C. Kieda, and S. Chouaib Human NK Cells Lyse Organ-Specific Endothelial Cells: Analysis of Adhesion and Cytotoxic Mechanisms J. Immunol., May 1, 2005; 174(9): 5573 - 5582. [Abstract] [Full Text] [PDF]
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 C. H. Yun, A. Lundgren, J. Azem, A. Sjoling, J. Holmgren, A.-M. Svennerholm, and B. S. Lundin Natural Killer Cells and Helicobacter pylori Infection: Bacterial Antigens and Interleukin-12 Act Synergistically To Induce Gamma Interferon Production Infect. Immun., March 1, 2005; 73(3): 1482 - 1490. [Abstract] [Full Text] [PDF]
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J. Regunathan, Y. Chen, D. Wang, and S. Malarkannan NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors Blood, January 1, 2005; 105(1): 233 - 240. [Abstract] [Full Text] [PDF]
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M. J. Smyth, J. Swann, J. M. Kelly, E. Cretney, W. M. Yokoyama, A. Diefenbach, T. J. Sayers, and Y. Hayakawa NKG2D Recognition and Perforin Effector Function Mediate Effective Cytokine Immunotherapy of Cancer J. Exp. Med., November 15, 2004; 200(10): 1325 - 1335. [Abstract] [Full Text] [PDF]
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S. Radhakrishnan, L. T. Nguyen, B. Ciric, D. Flies, V. P. V. Keulen, K. Tamada, L. Chen, M. Rodriguez, and L. R. Pease Immunotherapeutic Potential of B7-DC (PD-L2) Cross-Linking Antibody In Conferring Antitumor Immunity Cancer Res., July 15, 2004; 64(14): 4965 - 4972. [Abstract] [Full Text] [PDF]
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J. Brady, Y. Hayakawa, M. J. Smyth, and S. L. Nutt IL-21 Induces the Functional Maturation of Murine NK Cells J. Immunol., February 15, 2004; 172(4): 2048 - 2058. [Abstract] [Full Text] [PDF]
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J. A. Westwood, J. M. Kelly, J. E. Tanner, M. H. Kershaw, M. J. Smyth, and Y. Hayakawa Cutting Edge: Novel Priming of Tumor-Specific Immunity by NKG2D-Triggered NK Cell-Mediated Tumor Rejection and Th1-Independent CD4+ T Cell Pathway J. Immunol., January 15, 2004; 172(2): 757 - 761. [Abstract] [Full Text] [PDF]
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A. P. Junqueira-Kipnis, A. Kipnis, A. Jamieson, M. G. Juarrero, A. Diefenbach, D. H. Raulet, J. Turner, and I. M. Orme NK Cells Respond to Pulmonary Infection with Mycobacterium tuberculosis, but Play a Minimal Role in Protection J. Immunol., December 1, 2003; 171(11): 6039 - 6045. [Abstract] [Full Text] [PDF]
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M. J. Smyth, S. E. A. Street, and J. A. Trapani Cutting Edge: Granzymes A and B Are Not Essential for Perforin-Mediated Tumor Rejection J. Immunol., July 15, 2003; 171(2): 515 - 518. [Abstract] [Full Text] [PDF]
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