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BRIEF DEFINITIVE REPORT |
CORRESPONDENCE Marco Colonna: mcolonna{at}pathology.wustl.edu
 Top ABSTRACT RESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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© 2008 Gilfillan et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Cytotoxic lymphocytes, such as NK cells and CD8 T cells, require adhesion molecules to migrate into sites of infection and the tumor microenvironment and establish tight contact with virally infected and tumor cells (1). Moreover, in secondary lymphoid organs, adhesion molecules facilitate CD8 T cell and NK cell interactions with professional APCs, which induce their activation, expansion, and differentiation. Adhesion molecules act directly as signaling molecules, initiating intracellular pathways that trigger activation and adhesiveness of cytotoxic lymphocytes. They also act as accessory molecules, sustaining cellular contacts that are necessary for the TCRs and NK cell receptors to engage their cognate ligands and deliver intracellular signals.
CD8 T cells and NK cells express multiple adhesion molecules. Although several studies have addressed the importance of integrins (1), attention has recently focused on a novel Ig superfamily adhesion molecule called DNAX accessory molecule 1 (DNAM-1; also known as CD226). In humans, DNAM-1 is normally expressed on NK cells and CD8 T cells, as well as CD4 T cells and monocytes (2). In mice,
In summary, DNAM-1 appears to contribute to multiple innate and adaptive responses, which include (a) leukocyte migration; (b) activation, expansion, and differentiation of CD8 T cells and CD4 T cells; and (c) effector responses of T cells and NK cells. However, because cytotoxic lymphocytes express multiple adhesion molecules, it is difficult to determine whether DNAM-1 plays a unique role in these functions or is redundant. To address this question, we generated mice lacking expression of DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require co-stimulation by DNAM-1 when the antigen is presented by nonprofessional APCs, whereas DNAM-1 is dispensable in the presence of DCs. Thus, DNAM-1 can promote CD8 T cell responses to tumors expressing CD155 and/or CD112. In an analogous fashion, NK cells require DNAM-1 for elimination of tumor cells that are relatively resistant to NK cell–mediated cytotoxicity caused by the absence of other NK cell–activating ligands. In brief, DNAM-1 broadens the range of target cells that can activate CD8 T cells and NK cells and, hence, it may be critical for immunosurveillance of tumors and/or viruses that escape recognition by other activating or accessory molecules.
DNAM-1 is essential for CD8 T cell responses to nonprofessional APCs
40–50% of NK cells and all CD8 T cells constitutively express DNAM-1, whereas CD4 T cells express DNAM-1 preferentially upon activation (3). DNAM-1 binds to CD155, also known as Necl-5 or poliovirus receptor (4, 5). CD155 is expressed on epithelial cells, endothelial cells, and APCs. DNAM-1 also binds CD112 (Nectin-2), which is found on epithelial cells (4, 5). In vitro studies have shown that DNAM-1 triggers NK cell–mediated killing of tumor cells expressing CD155 and CD112 (4, 6–10). DNAM-1 also facilitates NK cell interaction with subsets of DCs that express CD155 (11). Moreover, DNAM-1 promotes co-stimulation of CD4 and CD8 T cells (3, 12, 13) and mediates adhesion of monocytes to endothelial cells facilitating transendothelial migration (14). DNAM-1 physically associates with the integrin lymphocyte function-associated antigen 1 (
Lβ2) and modulates its activation and capacity to bind intercellular adhesion molecule 1 (2, 15). Mechanistically, DNAM-1 recruits actin-binding proteins such as Discs-large and 4.1G, which rearrange actin cytoskeleton, promoting clustering of lymphocyte function-associated antigen 1 and formation of an adhesive complex that polarizes lymphocytes toward other cells (16).
RESULTS AND DISCUSSION
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ABSTRACT
RESULTS AND DISCUSSION
MATERIALS AND METHODS
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Normal development of DNAM-1–deficient mice
To generate DNAM-1–/– mice, we designed a targeting vector to replace exons two and three, encoding the start site and the first 129 amino acids of DNAM-1 with an MC1-neor gene flanked by loxP sites (Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20081752/DC1). One targeted E14.1 (129P2/OlaHsd) embryonic stem cell was injected into C57BL/6 blastocysts, and resulting chimeras were bred to C57BL/6 mice expressing a Cre transgene under the CMV promoter to delete the MC1-neor gene. The DNAM-1 deletion was then backcrossed onto a C57BL/6 background. Homozygote DNAM-1–/– mice were obtained at expected frequencies from intercrosses of heterozygote mice. DNAM-1–/– mice were phenotypically normal and healthy, and developed no gross abnormalities up to 1 yr of age. Flow cytometric analysis of DNAM-1–/– mice did not reveal major differences in the lymphoid cell populations (NK cells, CD8 T cells, CD4 T cells, DCs, plasmacytoid DCs, and B cells) in the spleen, thymus, peripheral blood, and lymph nodes or in bone marrow precursor populations (Figs. S1–S3; and not depicted). Therefore, DNAM-1 appears to be dispensable for development, including that of the immune system. Additionally, lack of DNAM-1 did not result in any compensatory change in the expression of CD96, the alternative lymphocyte receptor for CD155 (Fig. S1) (7, 17).
To assess the co-stimulatory function of DNAM-1 on CD8 T cells, we isolated T cells from WT and DNAM-1–/– mice, labeled them with CFSE, and stimulated them in vitro with APCs pulsed with graded doses of staphylococcal enterotoxin B (SEB) superantigen. As APCs, we used the B cell line A20, which expresses MHC class II, or A20 cells transfected with murine CD155 (mCD155; Fig. 1 E).
After 72 h, we harvested cells and evaluated CD8 T cell division. The percentage of dividing WT CD8 T cells was significantly higher when T cells were stimulated with A20-mCD155 rather than A20 parental cells (Fig. 1, A and C). In contrast, CD155 had a relatively minor effect on the proliferation of DNAM-1–/– CD8 T cells; the percentage of dividing DNAM-1–/– CD8 T cells was only slightly higher when SEB was presented by A20-mCD155 cells (Fig. 1, B and C). Similar results were obtained when the CD8 T cell proliferative response to SEB was measured by thymidine incorporation (Fig. 1 D). These data demonstrate a clear role of DNAM-1 in priming and expansion of CD8 T cells in response to a superantigen presented by B cells.
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. No significant differences in the frequency of IFN-–secreting T cells was observed after restimulation of DNAM-1–/– and WT lymph nodes with DCs (unpublished data), indicating that DNAM-1 deficiency had no marked impact on CD8 T cell priming. In contrast, fewer IFN-–secreting T cells were evident in lymph nodes from the DNAM-1–/– mice after restimulation with EL-4–mCD155 (Fig. 3 D), corroborating a role for DNAM-1 in promoting CD8 T cell activation and function in response to stimulation by nonprofessional APCs.
NK cells require DNAM-1 to eliminate targets resistant to cytotoxicity
Because CD155 is expressed on many tumor cells, DNAM-1 has been implicated as a major trigger for NK cell antitumor activity (4, 6–10). However, NK cells express additional receptors that mediate antitumor activity. NKG2D triggers NK cell surveillance against tumor cells expressing stress-induced MHC class I–related ligands such as MIC-A, MIC-B, and UL16-binding protein in humans, and Rae1, H60, and Mult1 in mice (19–21). Natural cytotoxicity receptors, such as NKp46, NKp44, and NKp30, have also been shown to mediate an important role in antitumor activity (22). The relative contribution of DNAM-1 versus other receptors has not been addressed in vivo. We first examined the cytotoxic ability of purified DNAM-1–/– and WT NK cells cultured with IL-2 to kill target cells in vitro. As target cells, we chose YAC-1 and B16F10. YAC-1 expresses the ligands for NKG2D, whereas B16F10 does not (23, 24); both targets express ligands for DNAM-1 (Fig. 4 A).
We found that IL-2–cultured NK cells efficiently killed YAC-1 cells whether or not they expressed DNAM-1 (Fig. 4 B). In contrast, although WT NK cells were capable of killing B16F10 tumors, DNAM-1–/– NK cells did not appreciably kill this tumor target (Fig. 4 C). Interestingly, DNAM-1–/– OT-1 CD8 T cells killed B16 cells pulsed with OVA peptide 257–264 less effectively than WT OT-1 CD8 T cells (Fig. 4 D), indicating that DNAM-1 may contribute to the cytotoxic function of both innate and adaptive lymphocytes.
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50% of NK cells expresses DNAM-1 (Fig. S1). Similar results were obtained in another experimental metastases model based on the injection of the mouse prostate carcinoma, RM-1, that also expresses mCD155 (unpublished data). At all tumor doses inoculated (103, 5 x 103, and 104 cells), DNAM-1–/– mice had significantly higher numbers of RM-1 lung metastases than WT mice (Fig. 5 B), although, again, mice depleted of NK cells had the highest numbers of metastases. Consistent with the metastases data, accelerated tumor growth was also observed after s.c. injection of B16F10 in DNAM-1–/– mice as compared with WT mice (Fig. 5 C). These results corroborate the increased susceptibility of DNAM-1–deficient mice to tumors because of the reduced function of NK cells.
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Concluding remarks
This report is the first describing mice specifically lacking DNAM-1 and definitively establishes an in vivo role for DNAM-1 during CD8 T cell and NK cell responses. Our results demonstrate that CD8 T cells require DNAM-1 for efficient stimulation by APCs that are weakly immunogenic, whereas a lack of DNAM-1 has no detectable impact on CD8 T cell stimulation by DCs. Thus, although DNAM-1 accessory function may be redundant in secondary lymphoid organs, it may be essential in peripheral tissues to promote optimal activation and effector functions of CD8 T cells that recognize their cognate MHC-peptide antigen on cells with limited expression of co-stimulatory ligands, such as tumor cells. Intraepithelial lymphocytes, 
T cells, and lamina propria lymphocytes may also depend on DNAM-1 for co-stimulatory signals from epithelial cells expressing CD155. Intraepithelial and T cells have been shown to rely on NKG2D-mediated co-stimulation and are in some cases directly activated by NKG2D ligands on tumor cells (25–27). Given this, DNAM-1 may either augment or, in some cases, compensate for NKG2D.
As indicated by our results with the B16F10 melanoma, expression of DNAM-1 enables NK cells to more efficiently kill tumor cells that are comparatively resistant to NK cell–mediated death because they lack NKG2D ligands. In contrast, DNAM-1 is dispensable for NK cell–mediated killing of highly susceptible targets that express NKG2D ligands, like YAC-1. Overall, our data suggest that DNAM-1 may play an important role in immunosurveillance against tumors and perhaps viral infections that are weakly immunogenic and refractory to NK cell–mediated cytotoxicity. Moreover, we have shown that DNAM-1 significantly contributes to CD8 T cell–mediated surveillance against tumor cells expressing CD112 and/or CD155. We and others have shown that T cells express at least one additional receptor for CD155, CD96, which has distinct functional characteristics (7, 17). Although it is possible that the lack of DNAM-1 is at least in part compensated by CD96, future studies will be necessary to determine the relative contributions of these two receptors to T cell and NK cell stimulation.
Genome-wide analysis of type I diabetes has recently revealed robust association of type I diabetes with a nonsynonymous single nucleotide polymorphism within the DNAM-1 gene (28). This observation, together with the observed expression of both DNAM-1 and CD155 in thymocytes (Fig. S3), suggests that DNAM-1–CD155 interactions may regulate the generation of autoreactive T cells, further emphasizing the importance of DNAM-1 in the immune response. We have shown that DNAM-1 considerably expands the range of cells that can activate CD8 T cells and NK cells. DNAM-1 is also up-regulated on CD4 T cells after Th1 differentiation but is down-regulated on Th0 and Th2 cells (3). How DNAM-1 influences CD4 T cell and perhaps T reg cell responses remains an open question.
In conclusion, this report provides the first demonstration that DNAM-1 promotes CD8 T cell co-stimulation and NK cell responses in vivo, broadening the spectrum of target cells that are effectively recognized. It has been shown that human CMV reduces expression of CD155 in infected cells through UL141 (29). Moreover, some tumors overexpress CD155 and release it as a soluble molecule (30), possibly to block DNAM-1 and prevent recognition of tumor cells. These mechanisms of evasion underscore the potential importance of DNAM-1–CD155 interactions in immunosurveillance against tumors and/or viral infections, particularly those that are weakly immunogenic because they do not engage major activating or accessory molecules.
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MATERIALS AND METHODS |
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TopABSTRACTRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Cell lines.
RM-1, B16F10, YAC-1, MC38-OVA, RMA-S, A20, and EL-4 cells were maintained in RPMI 1640 supplemented with 10% FCS. Stable transfectants of mCD155 were generated by electroporation of mCD155 cDNA. Positive cells were purified by FACS sorting. The MC38-OVA line was generated by retrovirally infecting the MC38 parental line with a pMIG/MSCV-IRES-eGFP plasmid-encoding membrane-bound OVA (provided by J. Villadangos, Walter and Eliza Hall Institute for Medical Research, Parkville, Australia).
Antibodies and reagents.
We generated the mAb 480.1 anti–mouse DNAM-1 (mDNAM-1) or mAb 3.1 anti–mouse CD96 (mCD96) by immunizing rats with RBL cells transfected with mDNAM-1 cDNA (RBL–mDNAM-1) or mouse CD96 cDNA (RBL-mCD96) and selecting hybridomas that reacted with 293–mDNAM-1 or 293-mCD96 transfectants but not with untransfected 293 cells. To generate the mAb 4.24 to mCD155, we immunized rats with a recombinant protein consisting of the mCD155 extracellular region fused to human Fc and selected hybridomas that reacted with RMA-S–mCD155 transfectants but not with untransfected RMA-S cells. Anti-asGM1 for depletion of NK cells was obtained from Wako Chemicals USA, Inc., and anti-CD8 mAb (53.6.7) was produced in our laboratory. Some groups of B6 mice were depleted of CD8+ T lymphocytes or NK cells in vivo by treatment with 100 µg anti-CD8 mAb or anti-asGM1 on days –1, 0 (day of i.v. tumor inoculation), and 7. These schedules effectively deplete T cell or NK cell subsets, as assessed by analysis using FITC-labeled mAbs. IL-2 was a gift from Novartis.
Cell preparations and FACS analysis.
Single-cell suspensions were prepared from lymph nodes and spleens and depleted of erythrocytes by ammonium chloride lysis. Lung lymphocytes were enriched in a Percoll (GE Healthcare) density gradient (45 and 67.5%) at 800 g for 15 min followed by ammonium chloride lysis. Cells were stained with anti-NK1.1–PE (PK136), -TCRβ–PECy5.5 (H57-597), -CD27–allophycocyanin (Lg.7F9), and -CD11b–FITC (M1/70). All antibodies were from eBioscience. Dead cells were excluded with 1 µg/ml fluorogold (Sigma-Aldrich) in the final wash. Cells were acquired on an LSR-II (BD). Analysis was performed using FlowJo software (Tree Star, Inc.). YAC-1, B16F10, RM-1, and MC38-OVA tumor cells were stained with biotinylated anti-mCD155 (clone 4.24) and purified anti-CD112 (clone 502-57; Abcam), followed by streptavidin-PE (eBioscience) and anti–rat–PE (Invitrogen), respectively. Cell acquisition and analyses were performed as described above. In some experiments, splenocytes or thymocytes were treated with Fc block (HB-197; American Type Culture Collection) and were stained with mAb 480.1 and anti-CD4, -CD8, -CD3, -NK1.1, -CD25, and -CD44 (all from BD). Samples were processed on a FACSCalibur and analyzed with CellQuest software (both from BD).
Stimulation with SEB.
Total T cells were purified from spleens of WT and DNAM-1–/– mice by positive selection with CD5 microbeads (Miltenyi Biotec). Contamination with CD5+ B cells was always <3% of the total cells recovered. Percentages of TCRVβ3, Vβ7, and Vβ8 within the CD4 and CD8 T cell compartments were always comparable in WT and DNAM-1–/– mice, as assessed by staining for CD4, CD8, and TCRVβ3, Vβ7, and Vβ8. A20 and mCD155-A20 cells were irradiated (11,000 rads) and pulsed for 4 h with serial dilutions of SEB (Toxin Technology Inc.). Cells were extensively washed and incubated with T cells labeled with CFSE (Invitrogen). After 72 h, cells were stained for CD4 and CD8 and analyzed by flow cytometry. In some experiments, cell proliferation was measured by [3H]thymidine incorporation.
Antigen stimulation.
OT-1 transgenic CD8 T cells were enriched from spleens of WT and DNAM-1–/– mice by negative selection with the CD8 T cell isolation kit (Miltenyi Biotec). Purity was monitored by staining with OVA257-264 tetramers (Beckman Coulter) and was always found to be >90%. EL-4 (American Type Culture Collection) and EL-4–mCD155 were irradiated (6,000 rads) and pulsed with SIINFEKL peptide (Bachem) for 3 h. Cells were extensively washed and incubated with purified OT-1 transgenic CD8 T cells for 72 h. Cell proliferation was measured by standard [3H]thymidine incorporation. Cell blasting was monitored by flow cytometry by recording changes in FSC/SSC.
In vitro and in vivo analyses of DCs.
Bone marrow cells were cultured with GM-CSF and analyzed at day 7 for expression of CD11c, mCD155, and CD86. Cells were challenged with 20 µg/ml poly I:C (InvivoGen), 1 µg/ml zymosan (Sigma-Aldrich), 6 µM CpG 1826 (QIAGEN), and 100 ng/ml LPS (Ultrapure LPS from Escherichia coli; List Biological Laboratories). Primary migrating DCs were visualized by painting ears of mice with CellTracker Green CMFDA (Invitrogen) dissolved in a mixture of acetone and dibutyl phthalate, as a source of irritation. CLNs were analyzed 48 h later by flow cytometry.
Detection of OVA-specific CD8 T cells in vivo.
WT and DNAM-1–deficient mice were immunized s.c. in the footpad with CFA and 100 nmol OVA peptide 257–264 (SIINFEKL). On day 7 or 8, mice were killed and popliteal lymph nodes were extracted. Lymph nodes were disrupted by scraping and were passed over 70-µm nylon cell strainers to make single-cell suspensions. 1.5 million lymph node cells were co-cultured in 24-well plates with 5 x 105 APCs either pulsed for 4 h with 1 µM SIINFEKL or left unpulsed. Two types of APCs were used: EL-4 cells transfected with CD155 or BMDCs (day 6 or 7 of GM-CSF culture). Co-cultures were incubated for 4 h at 37°C. 2 µM monensin was added to block cytokine export, and co-cultures were incubated overnight. Cells were surface stained with Fc receptor–blocking mAb 2.4G2, followed by anti-CD8–FITC (BD). To prepare for intracellular staining, cells were fixed in 2% paraformaldehyde (Sigma-Aldrich) and permeablilized in 0.5% saponin buffer. Cells were then stained with anti–IFN-–allophycocyanin (BD) and analyzed by flow cytometry.
NK cell in vitro assays.
Splenocyte suspensions were prepared as described above. For purification of NK cells by MACS, splenocytes were incubated with the NK cell isolation kit (Miltenyi Biotec), and cells were sorted by autoMACS (Miltenyi Biotec). NK cell media consisted of RPMI 1640 containing 10% FCS, β-2ME, nonessential amino acids, sodium pyruvate, L-glutamine, and penicillin/streptomycin. NK cells were expanded in NK cell media containing 1,000 U/ml IL-2 for 5 d. Cytotoxicity was assessed by standard 4-h 51Cr release assays.
In vivo tumor assays.
For lung metastasis assays, single-cell suspensions of B16F10 or RM-1 were prepared in PBS, and from 103 to 2 x 105 cells were injected i.v. in the tail vein of recipient mice. Lungs were harvested on day 14 and fixed in Bouin's solution, and tumor nodules were counted with the aid of a dissection microscope (model SZX7; Olympus). For s.c. tumor assays, mice were injected with various doses of B16F10 or MC38-OVA s.c., and tumor growth was monitored at least every second day using a caliper square to determine the product of two perpendicular tumor diameters.
Statistical analysis.
Statistical significance was assessed through the use of the Mann-Whitney rank sum test, as appropriate.
Online supplemental material.
Fig. S1 shows the generation of DNAM1–/– mice and of anti-mCD155 and -mDNAM1 antibodies. Fig. S2 shows NK cell percentages and maturation in WT and DNAM1–/– mice. Fig. S3 shows thymic T cell subsets in WT and DNAM1–/– mice. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20081752/DC1.
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Acknowledgments |
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This work was supported by National Institutes of Health grant R01AI056139-05 and Juvenile Diabetes Research Foundation grant 24-2008-938. We thank the National Health and Medical Research Council of Australia for the support of program grant 454569, a Senior Principal Research Fellowship (to M.J. Smyth), a Doherty Fellowship (to D.M. Andrews), and a CJ Martin Fellowship (to N.M. Haynes), as well as the Leukaemia Foundation of Australia for a research scholarship (to C.J. Chan).
The authors have no conflicting financial interests.
Submitted: 7 August 2008
Accepted: 30 October 2008
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REFERENCES |
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