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Differential Effects of the Rejection of Bone Marrow Allografts by the Depletion of Activating Versus Inhibiting Ly-49 Natural Killer Cell Subsets¹

Arati Raziuddin^*, Dan L. Longo, Llewellyn Mason, John R. Ortaldo, Michael Bennett^§ and William J. Murphy^2,*

^* Intramural Research Support Program, SAIC-Frederick, and Laboratory of Experimental Immunology, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702; National Institute on Aging, Baltimore, MD 21224; and ^§ University of Texas Southwestern Medical Center, Dallas, TX 75235

	Abstract

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Natural killer cells mediate the specific rejection of bone marrow cell (BMC) allografts in lethally irradiated mice. The Ly-49 family of molecules present on subsets of murine NK cells appears capable of binding class I MHC molecules, resulting in transmission of an inhibitory signal to the NK cell. These Ly-49 family members have been shown to have an immunoreceptor tyrosine-based inhibitory motif that is responsible for the inhibitory signal. However, a new Ly-49 family member was found that lacks this motif, Ly-49D, and evidence suggests that this may be an activating receptor. We therefore compared the role of the activating Ly-49 member with NK cells bearing inhibitory Ly-49 receptors in BMC rejection. Depletion of Ly-49D⁺ NK cells in H-2^b mice abrogated their ability to reject H-2^d BMC allografts. Similarly, Ly-49C⁺ NK cells also were shown to mediate the specific rejection of H-2^d BMC. When both subsets were depleted, an additive enhancement of BMC engraftment was observed, indicating that both subsets play a role in the rejection of allogeneic H-2-homozygous H-2^d BMC. However, rejection of H-2^{b x d} or D8 (H-2^b, D^d transgene) BMC allografts was unaffected by Ly-49C⁺ NK cell depletion in H-2^b mice. In marked contrast, depletion of Ly-49D⁺ NK cells in H-2^b mice totally abrogated the rejection of H-2^{b x d} heterozygous BMC in support of in vitro data suggesting that Ly-49D⁺ NK cells receive activating signals. Therefore, NK subsets demonstrate a differential ability to reject H-2 homozygous and heterozygous BMC.

	Introduction

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Natural killer cells are a subpopulation of lymphocytes distinct from T and B cells that have the ability to lyse various tumor cells and virally infected cells without prior sensitization (1, 2, 3). NK cells also mediate rejection of bone marrow allografts but not solid tissue allografts, and they exhibit a phenomenon called "hybrid resistance" in which H-2-homozygous parental bone marrow cell (BMC)³ grafts are rejected by lethally irradiated F₁ hybrid mice (3, 4, 5, 6, 7). A family of receptors for MHC class I molecules belonging to the C-type lectin superfamily, called the Ly-49 family, has been found on NK cells. Several of these related molecules, Ly-49A, Ly-49C, and Ly-49G2, have been recently cloned and characterized (8, 9, 10, 11). Binding of these receptors results in inhibitory signals preventing cytotoxicity of the recognized target by the NK cell (10). However, the vast majority of studies characterizing these subsets have used in vitro binding or cytotoxicity assays. The in vivo role(s) of these subsets and the mechanism by which they detect and reject allogeneic BMC remain undefined. According to the "missing self" hypothesis, NK cells will lyse target cells (i.e., foreign BMC) unless they receive inhibitory signals through receptors on the NK cell that recognize self class I molecules (7, 8, 9, 10, 11). However, it appears that multiple NK cell subsets with different Ly-49 receptors specific for class I MHC determinants other than self are present in mice. Ly-49A was the original Ly-49 molecule described, and this subset has been studied extensively in vitro. Ly-49A⁺ NK cells are inhibited by target cells expressing H-2D^d or H-2D^k and are therefore unable to lyse targets expressing those Ags (10, 12, 13, 14, 15). Expression of Ly-49A receptors has also been reported to be decreased in H-2^d mice (16, 17).

Interestingly, there has been no in vivo function of Ly-49A⁺ NK cells reported. Ly-49C molecules are negative signaling receptors for D^d or K^b MHC class I Ags (18). Ly-49C⁺ NK cells have been reported to play a role in the rejection of H-2^d BMC (18) both allogeneically and by hybrid resistance (19). Another inhibitory Ly-49 family member, Ly-49G2, recognizes both H-2D^d and H-2L^d on target cells in vitro, thus lysing H-2^b targets (9, 20). In agreement with the reported in vitro specificity, we have recently shown that in H-2^d mice Ly-49G2⁺ NK cells are responsible for the rejection of H-2^b bone marrow allografts in vivo (21). Recently, a subset of murine NK cells positive for Ly-49D has been identified by the 12A8 mAb (22). Sequence analysis indicates that Ly-49D is probably not a class I-specific inhibitory receptor but is an activating receptor due to the absence of an immunoreceptor tyrosine-based inhibitory motif (22). This has been confirmed by subsequent in vitro cytotoxicity studies (22).

We have conducted bone marrow transplantation experiments to examine the in vivo role of Ly-49D⁺ NK cells in bone marrow graft rejection. The results indicated that analogous with Ly-49C⁺ NK cells, Ly-49D⁺ NK cells also can mediate the rejection of H-2 homozygous allogeneic H-2^d bone marrow allografts in lethally irradiated H-2^b mice. However, Ly-49C⁺ and Ly-49D⁺ NK subsets are functionally distinct because unlike Ly-49C⁺ NK cells, Ly-49D⁺ NK cells do not play a role in hybrid resistance to parental H-2^d bone marrow grafts, but they do mediate the rejection of heterozygous (H-2^{b x d}) bone marrow grafts in H-2^b mice.

These results indicate that both activating and inhibitory Ly-49 subsets may complement each other in the rejection of bone marrow allografts but differ in the influence of the developmental milieu on their functional repertoire.

	Materials and Methods

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Mice

BALB/c (H-2^d), C57BL/6 (H-2^b), (BALB/c x C57BL/6)F₁ (CB6F₁, H-2^{b x d}), C.B-17 scid/scid (H-2^d, SCID), and C57BL/6 scid/scid (H-2^b, B6 SCID) mice were obtained from the Animal Production Area, NCI-Frederick Cancer Research and Development Center, Frederick, MD. All mice were kept under specific-pathogen-free conditions until use at 8 to 12 wk of age. D8 (H-2^b, D^d) transgenic mice were bred in the conventional colony of the Microbiology Department at the University of Texas Southwestern Medical Center.

NK cell isolation and cytometric analysis

NK cells from C57BL/6 and CB6F₁ mice were enriched from spleens of 8- to 12-wk-old animals, using a protocol that has been described earlier (21). Flow cytometric analysis was performed to determine the percentage of Ly-49D⁺, Ly-49A⁺, Ly-49C⁺, and Ly-49G2⁺ NK cells. Cells were incubated with mAb 12A8 (anti-Ly49D), YEL-48 (anti-Ly-49A), SW5E6 (anti-Ly-49C), or 4D11 (anti-Ly-49G2) for 30 min at 4°C, washed, and then incubated with directly fluoresceinated secondary Ab for 15 min. After two washes, the cells were fixed in 1% paraformaldehyde and analyzed on an EPICS flow cytometer (Coulter Electronics, Hialeah, FL).

Preparation of F(ab')₂ fragments of Abs

Fragmentation of IgG to F(ab')₂ using pepsin was as described elsewhere (23) with the following modifications: the pepsin concentration was 0.2 instead of 0.1 mg/ml; and the pH was 4.0 for fragmentation using citrate instead of acetate buffer (200 mM).

Assays for BMC engraftment

Groups of four to five conventionally housed recipient mice were injected with 80 to 200 µg of mAb 12A8 (anti-Ly49D), 500 µg of mAb SW5E6 (anti-Ly-49C and I), 200 µg of mAb 4D11 (anti-Ly-49G2), 200 µg of mAb YEL48 (anti-Ly-49A), 500 µg of mAb PK136 (anti-NK 1.1), or 0.2 ml of mouse or rat serum i.p., 2 days before irradiation. The engraftment of donor BMC was assessed by the following two methods because the assays for hemopoietic engraftment were performed by laboratories at two different institutions and to confirm that both assays yielded comparable results.

In vitro assay for hemopoietic growth. Two days after Ab injection, mice were lethally irradiated with a ¹³⁷Cs source (C57BL/6 at 1000 cGy; CB6F₁ at 1100 cGy) and were then injected with 5 x 10⁵ to 20 x 10⁵ BMC in 0.2 ml of HBSS. After 5 to 7 days, murine spleen cells were gently crushed in medium, and cell suspensions were prepared. The cell pellets were suspended in Iscove’s medium with 15% fetal bovine serum, 1% L-glutamine, and 100 U/ml of penicillin and streptomycin (Biowhittaker, Walkersville, MD). Spleen cells (1 x 10⁶) were plated in 0.3% Seaplaque agar (FMC Bioproducts, Rockland, ME) in 35-mm dishes containing optimal concentrations of recombinant murine cytokines (IL-3 (10 ng/ml) and GM-CSF (10 ng/ml)). Cytokines were obtained from the Biologic Response Modifiers Program Repository, Frederick, MD. Plates were incubated at 37°C for 7 days, and the colonies with >50 cells then counted (CFU-c). The data are presented as total CFU-c per spleen, which was obtained by multiplying number of colonies by the cellularity. Student’s t test was performed to determine whether the mean values were significantly (p < 0.05) different. Each experiment was performed at least three times with four mice per group.

In vivo assay for BMC engraftment. Two days after Ab injection, mice were lethally irradiated with ¹³⁷Cs source (C57BL/6 mice at 800 cGy) and were then injected with 3 x 10⁶ BMC in 0.5 ml via the lateral tail vein. Five days after marrow transfer, the proliferation of donor cells was assessed by measuring the splenic incorporation of 5-[¹²⁵I]iodo-2'-deoxyuridine ([¹²⁵I]IUdR, sp. act. 2200 Ci/mmol, Amersham Corp., Arlington Heights, IL), a DNA precursor analog. Each mouse was injected with 0.3 µCi of [¹²⁵I]IUdR i.p., 2 h later the spleens were removed and soaked in 70% ethanol for 24 h to elute the non-DNA radioactivity, and then the whole spleen radioactivity was counted in a gamma counter. The values are expressed as geometric means (95% confidence limits) of the percentage of injected [¹²⁵I]IUdR incorporated into the spleens. Parametric and nonparametric statistical analyzes were performed to determine whether the mean values were significantly (p < 0.05) different.

	Results

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Expression of Ly-49D on NK cells in C57BL/6 and CB6F₁ mice

Because the 12A8 mAb used cross-reacts with both the Ly-49D and Ly-49A Ags (22), we examined the expression of Ly-49D on resting splenic NK cells of C57BL/6 (H-2^b) and CB6F₁ (H-2^{b x d}) mice by staining with the 12A8 mAb and an anti-Ly-49A-specific mAb (YE148). As shown in Figure 1, 12A8⁺ cells (Fig. 1, A and B) are much more numerous than YE148 (Ly-49A)-positive cells (Fig. 1, C and D) in both H-2^b and H-2^{b x d} mice, suggesting that the Ly-49D Ag is expressed in both strains of mice in comparable amounts although fluorescence intensity seems lower in F₁ mice. Approximately 5% of the NK cells in both mice are double positive and express both Ly-49A and D markers (data not shown). Expression of other members of the Ly-49 family, i.e., Ly-49C (Fig. 1, E and F) and Ly-49G2 (data not shown), was also similar in the two strains.

View larger version (32K): [in this window] [in a new window]   FIGURE 1. Flow cytometric analysis of fresh splenic NK cells from C57BL/6 (A, C, and E) and CB6F1 mice (B, D, and F) following staining with mAbs to different Ly-49 Ags. NK cells were stained with mAb 12A8 (A and B), anti-Ly-49A mAb YE148 (C and D) or anti-Ly-49C mAb 5E6 (E and F) as described earlier (20). The dotted line represents staining with control Ab.

Ly-49 NK cell subset depletion studies were performed in C57BL/6 (H-2^b) mice. In vivo administration of Ly-49 mAb to C57BL/6 (H-2^b) mice followed by irradiation depleted all detectable Ly-49 NK cells within 48 h as determined by flow cytometry (results not shown). The splenic CFU-c assay was used to assess BMC engraftment in mice at either day 5 or day 8. The results presented in Table I demonstrate that the depletion of either Ly-49C⁺ or Ly-49D⁺ NK cells in C57BL/6 (H-2^b) mice significantly inhibited the ability of these mice to reject H-2^d bone arrow allografts. Interestingly, the magnitude of the inhibition of H-2^d bone marrow rejection was significantly greater after Ly-49D⁺ NK cell depletion than after Ly-49C⁺ NK subset depletion.

We next performed the BMT experiments in C57BL/6 (H-2^b) mice in which both Ly-49C⁺ and Ly-49D⁺ NK cells were depleted to determine whether removal of both subsets has an additive effect on the rejection of H-2^d BMC allografts. The data presented in Table I (Expt. 4) demonstrate that concurrent depletion of both Ly-49C⁺ and Ly-49D⁺ NK cells resulted in significantly (p < 0.01) greater abrogation of the ability of these mice to reject H-2^d allografts compared with the depletion of either of the subsets alone. These data suggest that Ly-49D⁺ NK cells and Ly-49C⁺ NK cell subsets from H-2^b mice can work in concert in mediating the rejection of H-2^d allografts.

Ly-49D⁺ NK cells do not mediate hybrid resistance to H-2^d or H-2^b BMC

F₁ hybrid mice can reject H-2 homozygous parental bone marrow grafts by a phenomenon called "hybrid resistance" (3, 4, 5, 6). We have shown previously that there was significant abrogation of the rejection of parental H-2^d or H-2^b bone marrow grafts in F₁ hybrid mice depleted of Ly-49C⁺ or Ly-49G2⁺ subsets, respectively (21). The in vivo depletion of Ly-49D⁺ NK cells in F₁ hybrid mice was followed by lethal irradiation and infusion of C.B17-SCID BMC (H-2^d) or B6 BMC (H-2^b). Depletion of Ly-49C⁺ and Ly-49G2⁺ NK cells was performed as controls. As expected, depletion of Ly-49C⁺ NK cells by mAb SW5E6 significantly inhibited the rejection of H-2^d BMC (Table II, Expts. 1 and 2), and depletion of Ly-49G2⁺ NK cells by the mAb 4D11 inhibited the rejection of H-2^b BMC (Table II, Expts. 3 and 4) by H-2^{b x d} F₁ hybrid recipients. However, removal of Ly-49D⁺ NK cells by administering mAb 12A8 in F₁ mice had no effect on the ability of these mice to reject either parental H-2^d (Table II, Expts. 1 and 2) or H-2^b marrow grafts (Table II, Expts. 3 and 4). Thus, Ly-49D⁺ NK cells mediate rejection of H-2^d bone marrow allografts in H-2^b mice but surprisingly do not play a role in the rejection of parental H-2^d BMC in F₁ mice despite being present (Fig. 1). These data suggest that Ly-49D⁺ and Ly49C⁺ NK cells have distinct functions in H-2^{b x d} F₁ mice, although both NK subsets act additively in the rejection of H-2^d BMC by H-2^b mice. Hence, Ly-49D⁺ NK cells unlike Ly-49C⁺ NK cells do not play a role in hybrid resistance.

Inhibitory interactions between Ly-49 family members and the MHC molecules they recognize lead to a failure to reject F₁ bone marrow that coexpresses a foreign MHC and a recognized MHC molecule. Thus, Ly-49C⁺ NK cells reject H-2^d bone marrow but not H-2^{b x d} bone marrow. To evaluate the function of Ly-49D⁺ NK cells in F₁ BMC rejection, we then examined the effect of Ly-49C⁺ and Ly-49D⁺ subset depletion on the rejection of H-2 heterozygous (H-2^{b x d}) BMC in H-2^b mice. C57BL/6 mice (H-2^b) were depleted of Ly-49D⁺ NK cells or Ly-49C⁺ NK cells, and 2 days later the mice were irradiated and infused with CB6F₁ (H-2^{b x d}) BMC. Results presented in Table IIIA demonstrate that depletion of Ly-49D⁺ NK cells abrogated the rejection of CB6F₁ hybrid (H-2^{b x d}) bone marrow grafts in H-2^b mice while depletion of Ly-49C⁺ NK cells had no effect. Similar results were obtained when experiments were performed with C57BL/6 SCID mice, which lack T cells and B cells, as BMC recipients (Table IIIB), indicating that this rejection was indeed due to NK cells (24). The results further support that inhibitory and activating NK subsets can be distinguished by function. Both subsets mediate the rejection of H-2^d allografts in H-2^b mice, but only the activating Ly-49D⁺ NK cells play a role in the rejection of F₁ hybrid (H-2^{b x d}) bone marrow grafts.

D8 mice are C57BL/6 (H-2^b) coexpressing the D^d transgene (25). It has been reported that the introduction of D^d transgene into H-2^b mice (i.e., D8) makes their BMC susceptible to rejection in H-2^b mice (25). We performed Ly-49D⁺ or Ly-49C⁺ NK subset depletion in H-2^b mice followed by BMT with D8 BMC (H-2^b, D^d) as donors to further compare the role of these subsets in BMC rejection based on recognition of D^d. In this experiment, [¹²⁵I]IUdR incorporation was assessed in the spleens of recipients 5 days after BMT as an indicator of hemopoietic cell proliferation and engraftment. The results presented in Table IV indicate that removal of Ly-49C⁺ NK cells had no effect on the rejection of D8 BMC (H-2^b, D^d) when compared with control groups. Hence, Ly-49C⁺ NK cells play no role in the rejection of D8 (H-2^b, D^d) BMC. However, the removal of the Ly-49D⁺ NK subset abrogated the rejection and promoted the engraftment of D8 (H-2^b, D^d) BMC comparable with that seen with depletion of all NK cells by the pan NK marker NK1.1. Therefore, Ly-49D⁺ NK cells in lethally irradiated C57BL/6 (H-2^b) mice mediate rejection to BMC expressing D^d whether the marrow is H-2 heterozygous (H-2^{b x d} or H-2^b,D^d) or homozygous (H-2^d).

To ascertain whether removal of Ly-49D⁺ cells is required for the abrogation of BMC rejection or whether blocking and interaction of Ly-49D with the BMC is sufficient, F(ab')₂ fragments of 12A8 were generated, and BMT was performed. Irradiated B6 mice received D8 BMC with or without F(ab')₂ fragments of 12A8. The results indicate that the administration of F(ab')₂ fragments of 12A8 partially abrogated the rejection of D8 BMC by B6 mice (Table V). In contrast, F(ab')₂ fragments of SW5E6 (anti-Ly-49C) had no effect, consistent with the in vivo depletion data. These results indicate that Ly-49D on the NK cell must interact with its target molecule for rejection to occur.

	Discussion

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View larger version (24K): [in this window] [in a new window]   FIGURE 2. Schematic representation of BMC graft rejection by inhibiting and activating Ly-49 NK cell subsets. In fully allogeneic BMT in H-2b mice, NK cells expressing inhibitory receptor Ly-49C are able to reject H-2d BMC due to the inability of H-2d to transmit an inhibitory signal because Ly-49C receptor does not recognize H-2d. In contrast, NK cells expressing activating receptor Ly-49D recognize H-2d and are activated and reject BMC. In hybrid resistance to parental H-2d BMC in F1 (H-2b x d) mice, NK cells expressing inhibitory receptor Ly-49C do not recognize H-2d and are not "turned off," thus rejecting BMC, while NK cells expressing activating receptor Ly-49D, being exposed to an H-2d environment during development, are functionally altered to H-2d and are no longer "activated" by H-2d. In the rejection of H-2d heterozygous BMC (H-2b x d or H-2d, Dd) NK cells expressing inhibitory receptor Ly-49C are "turned off" by Db on donor cells and are unable to reject heterozygous BMC, while NK cells expressing activating receptor Ly-49D are activated by recognizing Dd on donor cells and reject the BMC.

In F₁ hybrid (H-2^{b x d}) mice, Ly-49D⁺ NK cells are present in numbers similar to those of Ly-49C⁺ NK cells but do not mediate hybrid resistance to parental H-2^d bone marrow grafts. This is also in contrast to Ly-49C⁺ NK cells in F₁ mice that reject parental H-2^d bone marrow grafts. The data suggest that the functional phenotype of the Ly-49D⁺ subset is influenced by the developmental milieu. Ly-49D⁺ NK cells appear to be tolerized or functionally altered in F₁ mice, so that they no longer reject H-2^d bone marrow grafts. However, Ly-49D⁺ NK cells in F₁ mice are functional because preliminary data indicate that they mediate rejection of Dsp² allogeneic B10.R40 bone marrow grafts (data not shown).

The anti-Ly-49D mAb 12A8 cross-reacts with another Ly-49 member, Ly-49A (22). However, H-2D^d sends inhibitory signals to Ly-49A⁺ NK cells (10, 12, 13, 14, 15). It is therefore highly unlikely that Ly-49A⁺ NK cells play any role in the rejection of H-2^d BMC. This conclusion is supported by our observation that removal of Ly-49A⁺ NK cells by anti-Ly-49A mAb (A1) in H-2^d mice had no effect on the rejection of H-2^d bone marrow cells (Table I, Expt. 2). Indeed, preliminary data suggest that Ly-49A⁺ NK cells mediate rejection of H-2^b BMC allografts (data not shown). A similar situation exists with the anti-Ly49C mAb SW5E6, which has been reported to recognize Ly-49C and Ly-49I (26). More work must be performed to assess the in vivo functions of the two subsets.

Although our data indicate a role for Ly-49D⁺ NK cells in the rejection of homozygous or heterozygous H-2^d allografts, the normal physiologic function(s) of the Ly-49D⁺ NK subset and other Ly-49 members remains speculative. It has been reported that NK cells from Fas ligand or granzyme A gene knockout mice have impaired in vitro cytotoxicity against tumor targets but retain the capacity to eliminate bone marrow cells in vivo (27, 28, 29). This implies that cytotoxicity may not be the major mechanism of elimination of incompatible bone marrow cells. It is possible that differential cytokine production by NK cell subsets may play a role in bone marrow graft rejection or engraftment (30). This suggests that a normal physiologic role of these subsets may be in the homeostasis of hemopoiesis. We have observed that Ly-49C⁺ NK cells in H-2^d mice promote hemopoiesis by producing growth-promoting cytokines (granulocyte-macrophage-CSF) rather than growth-suppressing cytokines (IFN-) (30). It would be interesting to study the pattern of cytokines secreted by purified Ly-49 subset NK cells of various haptotypes after exposure to allogeneic, parental strain, or syngeneic BMC.

Given the rapid emergence of new members of the Ly-49 family, it seems likely that other NK subsets will be discovered. Whether the NK cell subsets will fall into two distinct functional groups based on the presence or absence of the immunoreceptor tyrosine-based inhibitory motif remains speculative. However, the data presented here suggest that the regulation of function of at least one NK subset may be influenced by the host milieu during development. Additional work is necessary to define that influence.

	Acknowledgments

 
We gratefully acknowledge the technical assistance of Ms. Kelli Taylor and Mr. Steven Stull. We are also grateful to Ms. Laura Knott for her secretarial assistance.

	Footnotes

 
¹ The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Animal care was provided in accordance with the procedures outlined in Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication 86-23, 1985).

² Address correspondence and reprint requests to Dr. William Murphy, SAIC-Frederick, NCI-FCRDC, Building 567, Room 210, Frederick, MD 21702.

³ Abbreviations used in this paper: BMC, bone marrow cell; CFU-c, colony-forming units-culture; [¹²⁵I]IUdR, 5-[¹²⁵I]iodo-2'-deoxyuridine.

Received for publication June 26, 1997. Accepted for publication September 17, 1997.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Ortaldo, J. R., R. B. Herberman. 1984. Heterogeneity of natural killer cells. Annu. Rev. Immunol. 2:359.[Medline]
2. Trinchieri, G.. 1989. Biology of natural killer cells. Adv. Immunol. 47:187.[Medline]
3. Bennett, M.. 1987. Biology and genetics of hybrid resistance. Adv. Immunol. 41:333.[Medline]
4. Murphy, W. J., C. W. Reynolds, P. Tiberghien, D. L. Longo. 1993. Natural killer cells and bone marrow transplantation. J. Natl. Cancer Inst. 85:1475.[Abstract/Free Full Text]
5. Cudkowicz, G., M. Bennett. 1971. Peculiar immunobiology of bone marrow allografts. II. Rejection of parental grafts by resistant F₁ hybrid mice. J. Exp. Med. 134:1513.[Abstract]
6. Murphy, W. J., V. Kumar, M. Bennett. 1987. Acute rejection of murine bone marrow allografts by natural killer cells and T cells: differences in kinetics and target antigens recognized. J. Exp. Med. 166:1499.[Abstract/Free Full Text]
7. Karre, K.. 1985. Role of target histocompatibility antigens in regulation of natural killer activity: a reevaluation and a hypothesis. R. B. Herberman, and D. M. Callewaert, eds. NK Mechanisms of Cytotoxicity by NK Cells 81. Academic Press, Orlando, FL.
8. Stoneman, E., M. Bennett, J. An, K. A. Chestnut, E. K. Wakeland, J. Scheerer, M. J. Siciliano, V. Kumar, P. A. Mathew. 1995. Cloning and characterization of 5E6(Ly-49C), a receptor molecule expressed on a subset of murine natural killer cells. J. Exp. Med. 182:305.[Abstract/Free Full Text]
9. Mason, L., S. L. Giardina, T. Hecht, J. Ortaldo, B. J. Mathieson. 1988. LGL-1: a non-polymorphic antigen expressed on a major population of mouse natural killer cells. J. Immunol. 140:4403.[Abstract]
10. Karlhofer, F. M., R. K. Ribaudo, W. M. Yokoyama. 1992. MHC class I alloantigen specificity of Ly-49⁺ IL-2-activated natural killer cells. Nature 358:66.[Medline]
11. Ljunggren, H. G., K. Karre. 1990. In search of the "missing self": MHC molecules and NK cell recognition. Immunol. Today 11:237.[Medline]
12. Wong, S., D. Freeman, C. Kellcher, D. Mager, F. Takei. 1991. Ly-49 multigene family: new members of a superfamily of type II membrane proteins with lectin-like domains. J. Immunol. 147:1417.[Abstract]
13. Smith, H. R. C, F. M. Karlhofer, W. M. Yokoyama. 1994. Ly-49 multigene family expressed by IL-2 activated NK cells. J. Immunol. 153:1068.[Abstract]
14. Daniels, B. F., F. M. Karlhofer, W. E. Seaman, W. M. Yokoyama. 1994. A natural killer cell receptor specific for a major histocompatibility complex class I molecule. J. Exp. Med. 180:687.[Abstract/Free Full Text]
15. Kane, K.. 1994. Ly-49 mediates EL4 lymphoma adhesion to isolated class I major histocompatibility complex molecules. J. Exp. Med. 179:1011.[Abstract/Free Full Text]
16. Karlhofer, F. M., R. Hunziker, A. Reichlin, D. H. Margulies, W. M. Yokoyama. 1994. Host MHC class I molecules modulate in vivo expression of a NK receptor. J. Immunol. 153:2407.[Abstract]
17. Olsson, M. Y., K. Karre, C. L. Sentman. 1995. Altered phenotype and function of natural killer cells expressing the major histocompatibility complex receptor Ly-49 in mice transgenic for its ligand. Proc. Natl. Acad. Sci. USA 92:1649.[Abstract/Free Full Text]
18. Yu, Y. Y. L., T. George, J. R. Dorfman, J. Roland, V. Kumar, M. Bennett. 1996. The role of Ly49A and 5E6 (Ly49C) molecules in hybrid resistance mediated by murine natural killer cells against normal T cell blasts. Immunity 4:67.[Medline]
19. Sentman, C. L., J. Hackett, V. Jr, V. Kumar, M. Bennett. 1989. Identification of a subset of murine natural killer cells that mediates rejection of Hh-1^d but not Hh-1^b bone marrow grafts. J. Exp. Med. 170:191.[Abstract/Free Full Text]
20. Mason, L. H., J. R. Ortaldo, H. A. Young, V. Kumar, M. Bennett, S. K. Anderson. 1995. Cloning and functional characteristics of murine large granular lymphocyte-1: a member of the Ly-49 gene family (Ly-49 G2). J. Exp. Med. 182:293.[Abstract/Free Full Text]
21. Raziuddin, A., D. L. Longo, L. Mason, J. R. Ortaldo, W. J. Murphy. 1996. Ly49G.2⁺ NK cells are responsible for mediating rejection of H2^b bone marrow allografts in mice. Int. Immunol. 8:1833.[Abstract/Free Full Text]
22. Mason, L. H., S. K. Anderson, W. M. Yokoyama, H. R. C. Smith, R. Winkler-Pickett, J. R. Ortaldo. 1996. The Ly-49D receptor activates murine NK cells. J. Exp. Med. 184:119.
23. Coligan, J. E., A. M. Kruisbeck, D. H. Margulies, W. Strober. 1994. Large scale fragmentation of IgG to F(ab')₂ using pepsin. Curr. Protocols Immunol. 1:2.8.6.
24. Murphy, W. J., V. Kumar, J. C. Cope. 1990. An absence of T cells in murine bone marrow allografts leads to an increased susceptibility to rejection by natural killer cells and T cells. J. Immunol. 144:3305.[Abstract]
25. Yu, Y. Y. L., J. Forman, C. Aldrich, B. Blazar, L. Flaherty, V. Kumar, M. Bennett. 1994. Natural killer cells recognize common antigenic motifs shared by H2D^d, H2L^d and possible H2D^r molecules expressed on bone marrow cells. Int. Immunol. 6:1297.[Abstract/Free Full Text]
26. Brennan, J., S. Lemiuex, J. D. Freeman, D. L. Mager, F. Takei. 1996. Heterogeneity among Ly-49C natural killer (NK) cells: characterization of highly related receptors with differing functions and expression patterns. J. Exp. Med. 184:2085.[Abstract/Free Full Text]
27. Baker, M., E. R. Podack, R. B. Levy. 1995. Perforin and Fas mediated cytotoxic pathways are not required for allogeneic resistance to bone marrow grafts in mice. Biol. Blood Marrow Transplant. 1:69.[Medline]
28. Aguila, H. L., I. L. Weissman. 1996. Mouse hematopoietic stem cells (HSC) are not direct targets of NK cells. Blood 87:1225.[Abstract/Free Full Text]
29. Miyazaki, T., A. Dierich, C. Benoist, D. Mathis. 1996. Independent modes of natural killing distinguished in mice lacking Lag3. Science 272:405.[Abstract]
30. Murphy, W. J., A. Raziuddin, L. Mason, V. Kumar, M. Bennett, D. L. Longo. 1995. NK cell subsets in the regulation of murine hemopoiesis I.5E6⁺ NK cells promote hemopoietic growth in H-2^d strain mice. J. Immunol. 155:2911.[Abstract]

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