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Multiple Deficiencies Underlie NK Cell Inactivity in Lymphotoxin- Gene-Targeted Mice¹

Mark J. Smyth^2,*, Ricky W. Johnstone^*, Erika Cretney^*, Nicole M. Haynes^*, Jonathon D. Sedgwick, Heiner Korner, Lynn D. Poulton and Alan G. Baxter

^* Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria, Australia; DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, CA 94304; Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; and Institut fuer Klinische Mikrobiologie, Immunologie und Hygiene, Erlangen, Germany

	Abstract

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We have evaluated the NK cell antitumor activity in lymphotoxin (LT)-deficient mice. Both NK cell-mediated tumor rejection and protection from experimental metastases were significantly compromised in LT--deficient mice. Analysis of LT--deficient mice revealed that the absolute number of TCR^- NK1.1⁺ NK cells was reduced in bone marrow and thymus, but with overall proportional decreases in other hemopoietic organs. In addition, the antitumor potential of TCR^- NK1.1⁺ cells, as determined by their lytic capacity and perforin expression, was reduced 1.5- to 3-fold in LT--deficient mice, as compared with wild-type mice. Combined defects in NK cell development and effector function contribute to compromised NK cell antitumor function in LT--deficient mice.

	Introduction

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Lymphotoxin (LT)³-, LT-, and TNF are structurally homologous cytokines within the TNF ligand superfamily (1). LT- and LT- are expressed by activated T and B lymphocytes and NK cells (2). LT- does not have a transmembrane domain and is secreted as a homotrimer (LT-3), but it can be retained on the cell surface in heterotrimeric complexes with LT- (3). Although LT-3 shares receptors with TNF (4), the predominant surface LT12 heterotrimer is the ligand for the LT-R (5). Recent studies in gene-targeted mice have revealed essential roles for TNF ligand superfamily molecules TNF, LT-, and LT- in secondary lymphoid organ structure and function (6, 7, 8, 9, 10), and this is probably largely attributable to downstream defects in production of T and B cell chemoattractants (11). The similar range of functions often attributed to TNF and LT are plausible, given that both TNF and LT- exist as soluble homotrimers (TNF-3, LT-3) and both can use the same surface receptors (4) and can signal through the same receptor(s) in vivo (12). However, the distinctly different outcomes observed when mice lack either TNF or LT function (9, 13, 14) provided a clear indication that, functionally, TNF and LT were substantially nonoverlapping cytokines.

Although the loss of TNF ligand superfamily molecules has focused on lymph node neogenesis and the relationship between T and B cells, very little information concerning their role in NK cell biology has been reported. TNF-deficient (TNF⁰)mice have normal numbers of functioning TCR^- NK1.1⁺ cells; however, we have recently demonstrated that TNF is critical for an appropriate NK cell accumulation in the peritoneum in response to inoculation with MHC class I^- tumor cells (15). Now, we report here that LT--deficient (LT-⁰) mice exhibit a profound defect in functional NK cell antitumor activity and that this can be attributed to a combination of defects in NK cell maturation and function.

	Materials and Methods

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Mice

Inbred C57BL/6 (B6) mice were purchased from The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. C57BL/6 perforin-deficient (B6.P⁰) mice (16), C57BL/6 gld (Fas ligand mutant), C57BL/6 TNF-deficient (B6.TNF⁰), C57BL/6 LT--deficient (B6.LT-⁰), and C57BL/6 LT--deficient (B6.LT-⁰) mice (9, 17, 18) were bred at the Austin Research Institute Biological Research Laboratories (ARI-BRL). Mice of 4 to 8 wk of age were used in all experiments, which were performed according to animal experimental ethics committee guidelines.

Cell culture and reagents

The mouse tumor cell lines were grown in culture as previously described (15, 19). Recombinant human IL-2 was a kind gift from Chiron (Emeryville, CA). Spleen cells were harvested from B6 and B6.LT-⁰ mice and depleted of CD3⁺ cells using anti-CD3 mAb (KT3, rat IgG2a) and C' (rabbit 1/30 dilution) as described (20). These cells were either tested directly for NK activity and Ab-dependent cellular cytotoxicity (ADCC) or cultured in IL-2 (1000 U/ml) for 4 days before examining their purity (>90% CD3^- NK1.1⁺) and cytotoxic capacity.

Flow cytometry

Cells from various organs were stained with anti-TCR-FITC (clone H57-597; PharMingen, San Diego, CA), anti-NK1.1-PE (NKR-P1C; clone PK136; PharMingen), anti-CD8-biotin (clone 53-6.7; PharMingen), and anti-CD4-APC (clone RM4-5; PharMingen). Bound Ab was detected with FITC-conjugated sheep anti-mouse-Ig (Silenus Laboratories, Hawthorn, Australia) and counterstained with anti-CD45R/B220-Biotin (clone RA3-6B2; PharMingen) and anti-NK1.1-PE. Biotinylated Abs were detected with streptavidin-tricolor (Caltag Laboratories, San Francisco, CA). Analysis was performed on a FACStar^Plus (Becton Dickinson, San Jose, CA). Resting spleen cells were prepared for sorting by incubation with anti-CD4 (clone 172.4) and anti-CD8 (clone 3.155) supernatants and lysis with rabbit C' (C-six Diagnostics, Mecquon, WI) resulting in 4- to 5-fold enrichment of NK cells. Remaining cells were then stained with TCR-FITC and anti-NK1.1-PE and TCR^-, NK1.1⁺ cells sorted on a FACStar^Plus. Final recovery of NK cells was 0.1% (B6) and 0.4% (B6.LT-⁰), with purities of 99% and 98%, respectively. Equal numbers of sorted cells were lysed for Western analysis, and 5 µg proteins were separated on SDS-10% polyacrylamide gels and electroblotted onto nylon membranes. Blots were probed with anti-perforin mAb, and relative perforin expression was measured using the Eagle Eye II gel documentation system (Stratagene, La Jolla, CA).

⁵¹Cr release assays

Lysis by resting and IL-2-activated spleen NK cells was assessed in 4-h ⁵¹Cr release assays against labeled YAC-1 or P815 target cells as previously described (15). For ADCC, trinitrophenyl (TNP)-labeled cells were used as targets as previously described (21). Lysis in the absence of anti-TNP mAb (mouse IgG2a) was subtracted to calculate ADCC. Each experiment was performed using triplicates. The results were recorded as LU₂₀/10⁷ cells and with resting spleen effectors were adjusted to account for the lower proportion of NK1.1⁺ cells in the B6.LT-⁰ mice.

Tumor control in vivo

NK cell function was examined in two different tumor models as described (15, 19). Firstly, groups of 5 to 10 mice were injected i.p. with RMA-S cells and observed daily for tumor growth for 100 days by monitoring the development of ascites in mice. In the second model, groups of five mice were injected s.c. with RM-1 tumor cells (2 x 10⁶), and tumors were established for 9 days. At this time, s.c tumors were surgically resected, and RM-1 cells were injected via the dorso-lateral tail vein. Mice were euthanized 14 days later, the lungs were removed and fixed in Bouin’s solution, and surface lung metastases were counted with the aid of a dissecting microscope. Control experiments were performed by inoculating mice with RM-1 cells i.v. and 14 days later counting lung metastases. The data were recorded as the mean (n = 5) number of lung colonies ± SE of the mean. Significance was determined by an unpaired t test to determine a two-tailed p value.

	Results and Discussion

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Defective class I^- tumor control by NK cells from LT-⁰ mice

Recently we demonstrated that MHC class I^- RMA-S tumor growth was controlled in the peritoneum by CD3^- NK1.1⁺ NK cells in a perforin-dependent manner (15). RMA-S cells inoculated i.p. were cleared 100-fold less effectively in B6.P⁰ mice and B6.LT-⁰ mice, compared with wild-type B6 mice (Ref. 15 and Fig. 1A). As previously reported (15), B6.TNF⁰ mice also had defective NK cell-mediated tumor rejection, although their defect was modest when compared, at low tumor doses (by day of death or number dead), with B6.LT-⁰ mice (Fig. 1A). The apparent lack of NK cell antitumor activity in LT-⁰ mice was then examined in a second model, where CD3^- NK1.1⁺ NK cells control RM-1 tumor colonization in the lung (19). A significantly greater number of lesions was observed in B6.LT-⁰ mice (p < 0.005) and B6.P⁰ mice (p < 0.0001), than in untreated B6 or B6.TNF⁰ mice, regardless of whether RM-1 was inoculated i.v. without (Fig. 1B) or with (Fig. 1C) prior s.c. RM-1 tumor challenge. The mean wet weight of the RM-1 tumors excised was not significantly different (data not shown).

View larger version (27K): [in this window] [in a new window]   FIGURE 1. A, Elimination of i.p. administered MHC class I- syngeneic RMA-S tumor in vivo is defective in B6.LT-0 mice. A, B6, B6.P0, B6.TNF0, B6.LT-0, and B6.gld mice (5–10/group) were injected i.p. with tumor cells (10 to 105) in 0.2 ml PBS as indicated. Individual mice are represented by each symbol. B, Protection from lung colonization of RM-1 tumor is deficient in B6.LT-0 mice. B6, B6.P0, B6.TNF0, B6.gld, or B6.LT-0 mice were inoculated i.v. with increasing numbers of RM-1 tumor cells (5 x 103), and 14 days later the lung tumor colonies were counted and recorded as the mean number of colonies ± SE. These mice served as controls for those in (C). C, B6, B6.P0, B6.TNF0, B6.gld, or B6.LT-0 mice were inoculated s.c. between the shoulder blades with RM-1 tumor cells (2 x 106), and tumors were allowed to establish for 9 days. Tumors were then resected, and 5 x 103 RM-1 cells were injected via the tail vein. Mice were euthanized 14 days later, and the lung tumor colonies were counted. Asterisks indicate the groups that are significantly different from B6-untreated mice (*, p < 0.005; **, p < 0.0001).

Reduced NK cell frequency and number in B6.LT-⁰ mice

NK cell numbers and proportions were analyzed in B6.LT-⁰, B6.TNF⁰, and B6.LT-⁰ mice by flow cytometry and compared with B6 mice (Table I). Consistent with previous reports (15), there was a 2- to 6-fold increase in total leukocyte numbers in peripheral blood, spleen, peritoneum, and thymus of B6.LT-⁰ and B6.LT-⁰ mice (data not shown). Despite this increase in total leukocyte numbers in B6.LT-⁰ mice, the percentage of TCR^- NK1.1⁺ cells in these organs was reduced by 30–70%. The decrease in the proportion of TCR^- NK1.1⁺ cells in each organ examined meant that, in some organs such as the thymus and bone marrow (BM), the absolute number of TCR^- NK1.1⁺ cells was reduced in B6.LT-⁰ mice by 37% and 48%, respectively (Table I). No such similar reductions in NK cell numbers were noted in B6.TNF⁰ and B6.LT-⁰ mice. The reduction in the proportions of NK1.1⁺ cells in B6.LT-⁰ mice could not simply be explained by modulated NK1.1 expression on NK cells since similar reductions (50%) in the proportion of other DX-5⁺, CD16⁺, and Ly-49⁺ (other NK cell markers) cells were noted in the spleens, BM, and peripheral blood of B6.LT-⁰ mice (data not shown). The reduction in BM TCR^- NK1.1⁺ cells is of particular interest, since these cells are believed to be the source of most NK1.1⁺ NK cells in immune responses (23) and NK cell differentiation is BM dependent. Interestingly, there was also a similar reduction in TCR⁺ NK1.1⁺ cells in B6.LT-⁰ BM (data not shown).

View this table: [in this window] [in a new window]   Table I. Relative proportions and numbers of NK cells in B6.LT-o mice

Reduced lytic capacity of NK cells from B6.LT-⁰ mice

We then compared the cytotoxic capacity of TCR^- NK1.1⁺ cells from B6.LT-⁰ mice with those from wild-type B6 mice on a cell per cell basis. TCR^- NK1.1⁺ cells were isolated from the spleens of these mice, and direct cytotoxicity and ADCC manifested by these unstimulated effectors were measured (Table II). The NK cells from the spleens of B6.LT-⁰ mice were 1.8-fold less active than spleen NK cells from B6 mice in both direct (vs YAC-1) and ADCC (vs P815) assays, as measured by LU₂₀. It should be noted that NK cells from B6.P⁰ mice display no lytic capacity in these same assays (data not shown). Furthermore, purified, IL-2-activated TCR^- NK1.1⁺ NK cells from B6.LT-⁰ mice were 1.5- to 2.0-fold less active than those from B6 mice against YAC-1, P815 (lymphokine-activated killer cell (LAK)), and TNP-labeled EL4 (ADCC) (Table II). Thus, TCR^- NK1.1⁺ NK cells from B6.LT-⁰ mice displayed a consistent reduction in all forms of cytotoxicity. In NK cells, perforin is the key cytotoxic granule molecule primarily responsible for their cytotoxic activities (24). Sorted TCR^- NK1.1⁺ spleen cells from B6.LT-⁰ mice had 1.44 ± 0.03-fold lower perforin expression than NK cells from wild-type B6 mice (Fig. 2). This reduced perforin expression may contribute to the reduced NK cell-mediated lysis of B6.LT-⁰ NK cells.

View this table: [in this window] [in a new window]   Table II. Reduced cytotoxic potential of NK cells from B6.LT-o mice

View larger version (21K): [in this window] [in a new window]   FIGURE 2. Western analysis of perforin (Pfp) expression in sorted B6.LT-0 TCR- NK.1.1+ cells (lane 1) or B6 TCR- NK.1.1+ cells (lane 2); or from whole spleen cells from B6.P0 mice (lane 3) or B6.granzyme B-deficient mice (lane 4). Molecular mass standards are shown (left) in kDa. The ratio expression of perforin in B6.LT-0 and B6 NK cells obtained from five separate Western blot experiments on two different populations of sorted cells was determined to be 1.44 ± 0.03, by gel densitometry.

This study has demonstrated that LT- is important for the effector functions of mature NK cells. Proportions and numbers of TCR^- NK1.1⁺ cells and NK cell lytic capacities were compromised in B6.LT-⁰ mice. We believe it is unlikely that a 2-fold reduction in NK cell cytotoxicity alone could completely account for the inability of B6.LT-⁰ mice to resist an i.p. challenge with RMA-S tumor cells. However, the combination of lower NK cell proportions and numbers (in BM) and reduced NK cell cytotoxicity might together contribute to defective tumor rejection. Although the NK cell parameters measured are indicators of NK cell development or effector function, they probably represent only part of the dysfunction of NK cells in LT-⁰ mice. In particular, it will be important to examine earlier progenitors of NK cells in LT- gene-targeted mice to determine whether there are specific points at which LT- function controls NK cell development. Of note, a novel subset of CD4⁺ CD3^- LT-⁺ fetal cells has been demonstrated to be instrumental in the development of lymphoid tissue architecture and some NK cells (25). Furthermore, gene targeting of the transcription factor Id2 supports the idea that a similar early population of gut-associated cells may be important for normal NK cell development (26). Of relevance to this issue are our ongoing studies that indicate that LT-⁰ mice exhibit almost normal NK cell function. This is despite similar levels of TNF production to that seen in B6.LT-⁰ mice (see above), and the absence of most LN. What distinguishes the LT-⁰ and LT-⁰ mice is the presence of mesenteric lymph node in the latter (8), indicating some maturation of gut-associated lymphoid elements and quite possibly the maintenance of events critical to the development of functional NK cells (25, 26, 27).

The dependence of chemokine production, at least that necessary for T and B cell localization in the spleen, on both TNF and membrane LT12 (11) suggests that defects of NK cell movement may also be a contributory factor to poor in vivo NK cell antitumor function in LT-⁰ mice. Indeed, we have evidence that, like B6.TNF⁰ mice (15), the migration and accumulation of NK cells is defective, at least following peritoneal tumor inoculation in B6.LT-⁰ mice (data not shown). However, unlike in B6.LT-⁰ mice, the NK cell function in B6.TNF⁰ mice is defective only at this site (Fig. 1). It remains to be determined whether there is a contribution of leukocyte movement to the more marked and global NK cell defects in B6.LT-⁰ mice. Knockout and transgenic mice and in vitro culture systems have proven useful in identifying critical signals required for NK development and proliferation (28). Using these culture systems to compare NK cell development in mice gene targeted for various TNF ligand superfamily molecules should be informative.

	Acknowledgments

 
We are grateful for the care and assistance of the staff at the ARI-BRL.

	Footnotes

 
¹ M.J.S. is currently supported by a National Health and Medical Research Council of Australia (NH&MRC) Principal Research Fellowship and by project grants from the NH&MRC. J.D.S. received support (through December 1998) from the NH&MRC and the National Multiple Sclerosis Society of Australia. R.W.J and A.G.B. are recipients of R. Douglas Wright Fellowships from the NH&MRC, and A.G.B. is supported by a program and project grants from the Juvenile Diabetes Foundation, Diabetes Australia, and the NH&MRC. L.D.P. is a recipient of a NH&MRC Australian Postgraduate Research Award. DNAX Research Institute is supported by Schering-Plough Corporation.

² Address correspondence and reprint requests to Dr. Mark Smyth, Cellular Cytotoxicity Laboratory, The Austin Research Institute, Studley Road, Heidelberg, Victoria, 3084, Australia. E-mail address:

³ Abbreviations used in this paper: B6, C57BL/6; BM, bone marrow; FasL, Fas ligand; LU₂₀, the number of effector cells required to lyse 20% of the target cells; LT, lymphotoxin; LT-⁰, LT--deficient; LT-⁰, LT--deficient; P⁰, perforin-deficient; TNF⁰, TNF-deficient; TNP, trinitrophenyl; ADCC, Ab-dependent cellular cytotoxicity; LAK, lymphokine-activated killer cell.

Received for publication May 18, 1999. Accepted for publication May 25, 1999.

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