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The Journal of Immunology, 2006, 176: 7165-7169.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Dominance by an MHC-Independent Inhibitory Receptor Compromises NK Killing of Complex Targets1

Joseph A. Wahle*, Kim H. T. Paraiso*, Amy L. Costello*, Emily L. Goll*, Charles L. Sentman{dagger} and William G. Kerr2,*

* Department of Interdisciplinary Oncology, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612; and {dagger} Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03755


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Inhibitory receptors that recognize MHC class I molecules regulate NK cell responses and self-tolerance. Recent evidence indicates that self-ligands not present in the MHC locus also can modulate NK function. In this study, we show that an inhibitory receptor that recognizes an MHC-independent ligand is over expressed in SHIP–/– mice at all stages of NK development and differentiation. Overexpression of this receptor compromises key cytolytic NK functions, including killing of allogeneic, tumor, and viral targets. These results further demonstrate the critical role that SHIP plays in regulation of the NK receptor repertoire and show that regulation of MHC-independent inhibitory receptors is crucial for NK recognition and cytolysis of complex targets.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Natural killer cells distinguish normal cells from those altered by infection, stress, or transformation via inhibitory receptors that detect self-ligands and activating receptors that recognize MHC-like ligands expressed by tumor cells, virally infected cells, or cells with DNA damage (1, 2, 3, 4). Recognition of self by NK cells is layered and involves the recognition of MHC class I (MHC-I)3 molecules (5) or non-MHC ligands, such as CD48 and Ocil/Clr-b, via the nonclassical receptors 2B4 and NKR-P1D, respectively (6, 7, 8).

2B4 is a member of the CD2 Ig superfamily that includes signal lymphocyte activation molecule and CD48 (9). Studies originally indicated an activating role for 2B4, although most of these studies were performed in vitro using Ab ligation experiments (10, 11, 12). A more definitive role for 2B4 was recently demonstrated through the generation of a 2B4 mutant mouse, in which an inhibitory role was identified (13). Although the signaling pathways that control responses following 2B4 ligand engagement have yet to be defined in their entirety, several participating signaling components have been defined, including SAP, EAT-2, FynT, SHP1, PI3K, and SHIP (11, 13, 14, 15, 16). We have shown previously that SHIP is critical for maintenance of NK receptor (NKR) repertoire diversity in the peripheral NK compartment (17). In this study, we demonstrate that SHIP deficiency causes deregulation of 2B4 surface expression and signaling such that cytolysis of complex targets is compromised.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Animals

SHIP–/– mice were created previously in our laboratory (17) and were maintained by intercrossing SHIP+/– mice (F10 to the C57BL6/J background). All NK repertoire, acute bone marrow (BM) graft rejection studies, and tumor cytolysis studies were performed with SHIP–/– and wild-type (WT) littermates between 6 and 9 wk of age. All studies were performed in accordance with the guidelines and approval of the Institutional Animal Certification and Use Committee at the University of South Florida.

Acute BM engraftment assays

Assay of BM engraftment by the splenic I-iodo-deoxyuridine (IUdR) uptake assay has been described previously (17). Briefly, SHIP+/+, SHIP–/–, and syngeneic BL6 hosts were irradiated (950 rad) and then received 5 x 106 whole BM cells from allogeneic or syngeneic donors as indicated. Engraftment of allogeneic BM in SHIP+/+ or SHIP–/– hosts was quantitated by i.v. injection of 3 µCi of 125I-labeled UdR 4 days post-BM transplantation. On the fifth day post-BM transplantation, the spleens were removed and 125I-labeled uptake quantitated with a gamma counter (Wizard1470; PerkinElmer).

Ab staining and flow cytometry

CD16/32 was coincubated with the samples to block FcR binding. Primary Abs included NK1.1 and 2B4, which were purchased from BD Pharmingen. C7 (hamster IgG1) was purchased from eBioscience. 3D10 (rIgG1) was conjugated to biotin and used for staining Ly49H as described previously (18). Samples were acquired on a FACSCalibur (BD Biosciences) and analyzed using FlowJo software (version 6.3; Tree Star). NK Lin staining consisted of NK1.1+ and lineage– (IgM, CD3, TCR-beta, and Gr-1) cells.

Lymphokine-activated killer (LAK) cultures and cytolysis assays

NK cells were enriched from whole splenocytes through the use of a mouse NK cell enrichment kit (Milteny Biotec). LAK cells were cultured for 7 days in the presence of 2000 U/ml human rIL-2 (Proleukin; Chiron). On day 7, a standard 4-h chromium release assay was performed. Briefly, target cells were loaded with 100 µCi of 51Cr per 1 x 106 cells for 90 min at 37°C. E:T ratios of 60:1, 20:1, and 6.33:1 were used with 3000 target cells. The cells were incubated together at 37°C for 4 h. Supernatants were collected and measured for radioactivity on a gamma counter (Wizard1470; PerkinElmer).

Ab blocking experiments

Target cells were first loaded with 51Cr. Both the target cells that were to be blocked with anti-CD48 as well as the unblocked controls underwent Fc blocking. Target cells were then incubated with anti-CD48 (clone BCM1; eBioscience) at 1 µg per million cells for 15 min before incubation with effector cells. A normal cytoxicity assay was then performed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
We have further defined the role of SHIP in the NKR repertoire by placing the SHIP mutation on a defined genetic background (C57BL6/J). The peripheral NK compartment of SHIP–/– mice (C57BL6/J) is disrupted with a profound under-representation of inhibitory NKR specific for MHC-I (data not shown). Only two NKR, 2B4 (Fig. 1) and NKR-P1D (data not shown), are found to be overexpressed or overrepresented in NK cells of SHIP–/– mice. Intriguingly, both of these receptors are specific for MHC-independent ligands. To further determine the effect of SHIP deficiency on 2B4 expression, we examined various stages of NK cell maturation and activation. Our initial analysis included both mature splenic NK cells as well as immature BM NK cells; in both instances, 2B4 is overexpressed on the surface of SHIP–/– NK cells, compared with NK cells from WT littermates (Fig. 1, A and B). We further examined 2B4 status using both in vivo polyinosinic acid-activated NK cells and in vitro-activated LAK cells. Consistent with our analysis of freshly isolated NK cells, in vivo-activated (Fig. 1C) and in vitro-activated (Fig. 1D) SHIP–/– NK cells exhibit increased surface density of 2B4, compared with WT controls. In addition, we created chimeric mice by transplanting 5.1 (WT) and 5.2 (SHIP–/–) BM into the same lethally irradiated host. In these assays, we found that 2B4 expression is increased in the 5.2 SHIP–/– NK cells, compared with 5.1 WT NK cells present in the same chimera (Fig. 1E). This indicates that SHIP has an impact on 2B4 expression that is intrinsic to the NK lineage. Thus, SHIP is required to maintain normal expression of 2B4 on the cell surface, indicating that SHIP regulates expression of NKR for not only MHC ligands, but also for MHC-independent ligands. Moreover, SHIP performs this role at multiple stages of NK development and differentiation.


Figure 1
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  		FIGURE 1. 2B4 status is altered in SHIP–/– NK cells. Representative overlays of 2B4 histograms after backgating on NK1.1+Lin– cells. Bar graphs represent mean fluorescence intensity of at least three separate animals. (*, p < 0.05, n = 3; Student’s two-tailed t test) SHIP–/– (red), WT (blue) (A), immature BM NK cells (B), mature splenic NK cells (C), in vivo polyinosinic acid-stimulated NK cells (D), in vitro IL-2-stimulated LAK cells, and splenic NK cells (E) from BM chimera mice.

 
Recently, 2B4 has been shown to function as an important inhibitory receptor in vivo (6). Thus, we speculated that the increased surface density of this inhibitory receptor might skew the balance of inhibitory and activating signals received by SHIP–/– NK cells and thereby alter key cytolytic functions. To examine the impact of 2B4 overexpression on SHIP–/– NK function, we first examined NK cytolysis of tumor cells mediated by the activating receptor NKG2D. Studies to date indicate that NKG2D is the critical receptor for recognition and killing of cells that express Rae1, H60, or Mult1. To examine whether cytolysis of tumor targets that express the NKG2D ligand Rae1 is compromised in the SHIP–/– NK compartment, we generated LAK cells. Intriguingly, we find that NK cell recovery in SHIP–/– LAK cultures is significantly better than that of WT cultures prepared in a similar manner (p < 0.05), suggesting that SHIP deficiency may enhance cytokine-stimulated NK cell survival and/or proliferation ex vivo (Fig. 2A). Flow cytometric analysis of these LAK cells revealed that surface expression of NKG2D on activated NK cells from SHIP–/– mice is comparable to that of WT controls prepared in an identical manner (Fig. 2B). The surface density of 2B4 remained elevated in SHIP–/– NK cells, as shown above (Fig. 1D). The cytolytic activity of the activated NK cells was then determined in a standard 4-h chromium release assay against RMA cells expressing the NKG2D ligand Rae1. Despite equal surface expression of NKG2D on SHIP–/– and WT LAK cells, we find that cytolysis of RMA Rae1-transfectants by SHIP–/– NK cells is profoundly compromised relative to WT NK cells at all E:T ratios tested (Fig. 2C). In fact, only at the highest E:T ratio, 60:1, was cytolysis of Rae1+ RMA cells by SHIP–/– LAK cells significantly higher than background cytolysis observed for parental RMA cells. No significant killing of parental RMA cells, which lack the Rae1 Ag, was seen for either SHIP–/– or WT NK cells, confirming the specificity of this assay for the NKG2D ligand Rae1. The fact that NKG2D expression levels are comparable in SHIP–/– and WT LAK cells, whereas NKG2D-mediated cytolysis is profoundly compromised in SHIP–/– NK cells, suggests that hyporesponsiveness in SHIP–/– NK cells could be due to increased expression and/or inhibitory signals from 2B4 engaging its ligand.


Figure 2
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  		FIGURE 2. Compromised NKG2D-mediated cytolysis of Rae1+ tumor targets by SHIP–/– NK cells and restoration by CD48 blockade. A, Percentage of IL-2 activated LAK cells recovered from four separate experiments are shown (*, p < 0.05; n = 4; Student’s two-tailed t test). B, NKG2D status of 7 day LAK cells for SHIP–/– (blue) and WT (green), and isotype control (red). C, Standard 4-h chromium release assays were performed with SHIP–/– and WT LAK cells. RMA cells with and without Rae1 transfectants were used as targets. Percent lysis is indicated on the left axis and the E:T ratios across the bottom axis (*, p < 0.05 for cytolysis of Rae1+ RMA cells by WT LAK cells compared with SHIP–/– LAK cells; +, p < 0.05 for cytolysis of RMA cells, compared with Rae1+ RMA cells by SHIP–/– LAK cells). D, Cytolysis of Rae1+ RMA cells with and without blocking of CD48 on target cells in a standard 4-h chromium release assay (*, p < 0.05 for cytolysis of blocked Rae1+ RMA cells by SHIP–/– LAK cells, compared with WT LAK cells; +, p < 0.05 for the cytolysis of blocked Rae1+ RMA cells vs unblocked Rae1+ RMA cells by SHIP–/– LAK cells).

 
To examine whether altered 2B4 signaling was causing this hyporesponsiveness, we tested whether antagonizing the 2B4–CD48 interaction restores NKG2D-mediated killing. Flow analysis has shown that CD48 expression is ubiquitous on the RMA target cells (data not shown). Incubation of targets with an anti-CD48 Ab was able to restore SHIP–/– LAK killing to WT levels (Fig. 2D). In three independent standard 4-h chromium release assays where we tested killing of Rae1+ RMA transfectants in the presence or absence of anti-CD48, we have repeatedly observed a statistically significant enhancement of SHIP–/– killing. Although some increase in WT killing due to CD48 blocking occurred, it was dramatically less than that observed with CD48 blockade in SHIP–/– LAK cytolysis assays. In fact, in all but one E:T ratio, 20:1, the killing by SHIP–/– LAK cells was not significantly different from that of killing by WT LAK performed in the presence of CD48 blockade. The ability to restore SHIP–/– LAK cytotoxicity against Rae1+ RMA targets by blocking the 2B4–CD48 interaction suggests that 2B4 has a dominant inhibitory role in the SHIP–/– NK compartment.

A recent study indicated NKG2D plays a prominent role in the ability of mice to reject MHC-mismatched BM grafts in an acute fashion (19). Previously, we found that the NK repertoire disruption observed in SHIP–/– mice on a mixed 129Sv/BL6 background led to an inability to reject H-2d and H-2s BM grafts that are completely MHC mismatched. We attributed engraftment in 129/BL6 SHIP–/– mice to overrepresentation of Ly49A and C (17). However, Ly49A and Ly49C are not overrepresented in SHIP–/– mice on a C57BL6 background, suggesting that rejection of allogeneic BM grafts might not be compromised in SHIP–/– mice on this defined background. Nonetheless, these SHIP–/– (BL6) mice might remain permissive for engraftment of MHC-mismatched BM grafts owing to the compromised NKG2D-mediated cytolysis that we observed above. This appears to be the case, as SHIP–/– mice on a C57BL6 background are still permissive for engraftment of BM from several different donors with full MHC mismatches (Fig. 3). Initially, we transplanted SHIP–/– (BL6) hosts with H-2d BALB/C BM and measured acute engraftment by the splenic IUdR assay used previously (17). As was observed in 129/BL6 SHIP–/– mice, (17) we find that BALB/C H-2d BM engrafts the SHIP–/– (BL6) cohort but is rejected by their WT littermates. Subsequently, we tested engraftment of BM from a variety of other donors with full MHC-I mismatches (H-2p, H-2r, H-2f, and H-2u) not analyzed previously and found that SHIP–/– (BL6) mice are also permissive for engraftment by BM from these donors (Fig. 3). This broad defect in rejection of different MHC-mismatched donors is consistent with the compromised NKG2D-mediated killing we observed above because NKG2D-mediated cytolysis exhibits no dependence on MHC haplotype.


Figure 3
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  		FIGURE 3. Allogeneic BM rejection assay. Splenic IUdR uptake in F9/10 x C57BL/6 SHIP–/–, and WT recipients transplanted with H-2d donor BM cells, F6 x C57BL/6 SHIP–/– and WT recipients transplanted with H-2f, H-2p, H-2u, or H-2r donor BM cells. Host (H) and donor (D) strain are shown for each transplant. All +/+ (WT) and –/– (SHIP–/–) mice are H2B (*, p < 0.05).

 
The ligand for Ly49H was recently identified as the CMV-encoded membrane protein m157 (18, 20). Because SHIP–/– NK cell killing of targets that express ligands for NKG2D is compromised, we postulated that killing of CMV m157+ targets might be similarly disabled. To test this, we examined the ability of LAK cells from SHIP–/– and WT mice to kill BaF3-m157+ transfectants (Fig. 4). As with NKG2D, we find that ex vivo activation of SHIP–/– NK cells with IL-2 restores Ly49H to a surface density essentially identical with that in WT controls (Fig. 4A). In standard 4-h chromium release assays, SHIP–/– LAK cultures showed severely diminished cytolysis of m157+ targets at all E:T ratios tested (Fig. 4B). Killing in this assay was confirmed as being specific for the m157 Ag, because no cytolysis of BaF3 parental cells was observed (Fig. 4B).


Figure 4
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  		FIGURE 4. Compromised Ly49H-mediated cytolysis of CMV m157+ viral targets by SHIP–/– NK cells and restoration by CD48 blockade. A, LAK cells were incubated with anti-NK1.1, CD3, and Ly49H. Histograms are representative of the status of Ly49H in WT (green) and SHIP–/– (blue) LAK cells, compared with the isotype control (red). B, Cytolysis of BaF parental cells and BaF transfectants expressing the CMV m157 ligand by IL-2-activated LAK cultures from SHIP–/– mice or WT littermates in a standard 4-h chromium release assay. Percent lysis is on the left axis and E:T ratios across the bottom axis (*, p < 0.05 for cytolysis of m157+ BaF target cells by WT LAK, compared with SHIP–/– LAK; +, p < 0.05 for cytolysis of m157+ BaF cells, compared with BaF cells alone by SHIP–/– LAK). C, Cytolysis of m157+ BaF cells with and without blocking of CD48 on target cells in a standard 4-h chromium release assay (+, p < 0.05 for cytolysis of blocked vs unblocked m157+ BaF cells by SHIP–/– LAK cells; *, p < 0.05 for cytolysis of blocked m157+ BaF cells by WT LAK cells, compared with SHIP–/– LAK cells). All cytotoxicity experiments were done in triplicate and are representative of two or more experiments.

 
Given that 2B4 signaling compromises NKG2D-mediated killing by SHIP–/– NK cells, we also examined whether this might be the case for the killing of viral ligand-positive targets mediated by Ly49H. Flow analysis has shown that CD48 expression is ubiquitous on the BaF targets cells (data not shown). As was done for NKG2D, we measured NK cytolysis using a standard 4-h chromium release assay in the presence and absence of anti-CD48. In three separate experiments, incubation of the m157+ BaF targets with anti-CD48 before killing significantly restored SHIP–/– LAK killing (Fig. 4C). The significant enhancement of WT killing by blocking of CD48 also was seen at the 20:1 E:T ratio but is lower than that observed for all m157+ cytolysis assays performed with SHIP–/– NK cells (Fig. 4C). Thus, as with killing of tumor targets, killing of targets that express a viral ligand for an NK activating receptor is also compromised by 2B4 inhibitory signaling, further demonstrating that 2B4 is a dominant inhibitory receptor in the SHIP–/– NK compartment.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
In this study, we have shown that SHIP–/– NK cells exhibit overexpression of 2B4 throughout all stages of NK maturation and activation. Our functional studies indicate that increased 2B4 inhibitory signaling disrupts this balance such that key activating receptors, such as NKG2D and Ly49H, are unable to effectively promote cytolysis. Although the molecular mechanisms responsible for this imbalance remain to be defined, we propose two hypotheses to explain this altered function.

In our first hypothesis, we propose that the quantitative difference in 2B4 expression between SHIP–/– and WT NK cells leads to an increase in the basal level of 2B4 inhibitory signals received by an NK cell and thus alters the balance of activating and inhibitory signals forcing the cell toward hyporesponsiveness. Increased basal inhibitory signals from ubiquitous 2B4–CD48 interactions could compromise the ability of a SHIP–/– NK cell to respond efficiently to activating signals from either NKG2D or Ly49H. In that case, the role of SHIP is to limit the surface expression of 2B4 to a level that does not interfere with normal activating receptors effecting NK cytolytic function. Alternatively, we propose that there also could be a qualitative change in the 2B4 inhibitory signaling in SHIP–/– NK cells such that each 2B4 receptor delivers a more potent negative signal. Although the precise molecular mechanisms of 2B4 signaling have not been fully elucidated, key components in this signaling pathway have recently been identified. Of relevance to this study is that SHIP has been shown to be recruited to 2B4, suggesting that it can influence 2B4 signaling (11, 14, 15, 21). SHIP may, in fact, be recruited to 2B4 to oppose the actions of PI3K. Consistent with this, PI3K also is recruited to 2B4 where it can trigger the activation of downstream effectors, including AKT and phospholipase C{gamma} (14, 22). Thus, a lack of SHIP may lead to unopposed PI3K signaling at 2B4 and thus a qualitative difference in 2B4 signaling.

It also is quite probable that the above potential mechanisms could act in concert to disrupt the function of the SHIP-deficient NK cell. That is, a qualitative change caused by a lack of SHIP signaling at 2B4 may initiate a quantitative change by deregulating 2B4 surface expression. The initial qualitative change also could effect changes in expression of other signaling molecules that participate in 2B4 signaling and thus further altering inhibitory signals emanating from 2B4. In this manner, the SHIP–/– NK cell becomes locked into a "feed-forward" 2B4 inhibitory signaling mode rendering the cell hyporesponsive in the presence of its ligand CD48. Our findings extend SHIP’s regulation of the NKR repertoire to MHC-independent inhibitory receptors but also demonstrate that this seemingly minor component of NKR regulation is absolutely critical to normal cytolytic function in the NK compartment.


   Acknowledgments
 
Anti-Ly49H, as well as BaF3 and BaF-m157+ transfectants, were gifts from Wayne Yokoyama (Washington University, St. Louis, MO). Special thanks to Davina Mulchan for genotyping of our mice. We thank Sarah May for technical assistance in the early phases of this study. We also thank the Flow Cytometry Core at H. Lee Moffitt Cancer Center and Research Institute.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by National Institutes of Health Grants R01HL72523 and R01101748 and academic development funds from H. Lee Moffitt Cancer Center and the University of South Florida. W.G.K. is the Newman Family Scholar of the Leukemia and Lymphoma Society. Back

2 Address correspondence and reprint requests to Dr. William G. Kerr, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: kerrw{at}moffitt.usf.edu Back

3 Abbreviations used in this paper: MHC-I, MHC class I; BM, bone marrow; WT, wild type; IUdR, I-iodo-deoxyuridine; LAK, lymphokine-activated killer; NKR, NK receptor. Back

Received for publication March 13, 2006. Accepted for publication April 18, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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