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* Department of Immunology and Infectious Diseases, Harvard School of Public Health, and
Genetics Institute, Wyeth Research, Cambridge, MA 02140; and
Department of Medicine, Harvard Medical School, Boston, MA 02115
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chains and the IL-4R 
-chain, is selectively expressed in lymphoid tissues and has been shown to interact with the common 
chain (c)3 (1, 2, 3). Ligand binding to the IL-21R can transduce signals through Janus kinases 1 and 3, STAT1, STAT3, and STAT5 (1, 3). In vitro experiments demonstrated that human IL-21 acts as a costimulus in anti-CD3-mediated T cell proliferation and also as a promoter of the proliferation and maturation of NK cells from bone marrow progenitors. In contrast to the response of human NK cells to IL-21, murine in vitro experiments showed that IL-21 inhibited rather than enhanced the IL-15-dependent expansion of resting and activated NK cells. Murine IL-21 was able to enhance the effector function of previously activated NK cells but did not promote their viability in culture. In addition, we have recently generated IL-21R-deficient (IL-21R-/-) mice and found that these mice have normal lymphoid compartments. In particular, the IL-21R-/- mice had no NK cell deficiency or any defect in NK cell activation and cytolytic activity (4). Taken together, these results suggest that the biological effects of this cytokine may diverge between different species. The biological effects of IL-21 on B cells, another lymphoid population that expresses the IL-21R, has not been extensively characterized. Initial studies demonstrated that IL-21 costimulates human B cell proliferation induced by anti-CD40 Ab, whereas it inhibits proliferation induced by anti-IgM Ab and IL-4 (2). Recently, it has been shown that human IL-21 induces proliferation and inhibits apoptosis of the IL-6-dependent human myeloma cell lines ANBL-6, IH-1, and OH-2 (5). Because IL-21 seems to elicit contrasting responses from human and murine NK cells, we were interested in characterizing the effects of IL-21 on primary murine B cells to determine whether the biological role of IL-21 also diverges between human and murine B cells.
In this report, we demonstrate that, in contrast to that seen with human IL-21, murine IL-21 does not enhance the proliferation of anti-CD40 Ab-costimulated murine B cells, but does inhibit proliferation induced by anti-IgM Ab and IL-4. We also show that IL-21 induces the apoptosis of primary resting and activated B cells. Moreover, IL-21 can induce the apoptosis of primary B cells even in the presence of prosurvival costimulatory factors such as IL-4, LPS, or anti-CD40 Ab. We show that IL-21-induced apoptosis correlates with a down-regulation in the expression of Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family. Furthermore, the reconstitution of Bcl-xL or Bcl-2 expression, either by retroviral overexpression or by preactivation with anti-CD40 Ab, protects primary B cells from IL-21-induced apoptosis. These results suggest that murine IL-21 is an effector rather than inhibitor of murine B cell apoptosis whose potential physiological role may be controlling homeostasis of the B cell compartment.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice were obtained from Taconic Farms (Germantown, NY). IL-21R -/- mice on the C57BL/6 background were generated and maintained as previously described (4).
B lymphocyte preparation and culture
Splenic B lymphocytes were purified to 95% purity by depletion of CD43+ cells using MACS magnetic beads specific for CD43 (Miltenyi Biotec, Auburn, CA) per the manufacturer’s instructions. B lymphocytes were cultured at 1–2 x 106 cells/ml in RPMI 1640 supplemented as described previously (6). Recombinant IL-21 (R&D Systems, Minneapolis, MN) was added to indicated cultures at a concentration of 200 ng/ml. Anti-CD40 Ab (BD PharMingen, San Diego, CA) was added to indicated cultures at a concentration of 5 µg/ml. Anti-IgM Ab (F(ab')2 fragment; Southern Biotechnology Associates, Birmingham, AL) was added to indicated cultures at a concentration of 5 µg/ml. Recombinant IL-4 (PeproTech, Rocky Hill, NJ) was added to indicated cultures at a concentration of 10 ng/ml. LPS (Sigma-Aldrich, St. Louis, MO) was added to indicated cultures at a concentration of 10 µg/ml. Boc-Asp(OMe)-fluoromethyl ketone (Boc-D(OMe)-FMK; Calbiochem, La Jolla, CA) was added to indicated cultures at a concentration of 20 µM.
B cell proliferation assay
For stimulations, CD43-depleted splenic B cells were cultured in either 5 µg/ml anti-CD40 Ab or 5 µg/ml anti-IgM Ab and 10 ng/ml IL-4 in the presence of varying amounts of IL-21 (0–200 ng/ml). Proliferation was assessed by the incorporation of [3H]thymidine (50 µCi/well) during the last 18 h of a 90 h culture. Stimulations were conducted in triplicate.
Propidium iodide analysis
Lymphocytes were cultured as described in the figures, pelleted by centrifugation and fixed in 40% EtOH. The cells were treated with RNase A (50 µg/ml) for 45 min at 37°C and subsequently stained with 700 mM propidium iodide in 3.8 x 10-2 M sodium citrate. Analysis was performed on a FACScan flow cytometer (BD Biosciences, Mountain View, CA).
Annexin V staining
Lymphocytes were cultured as described in the figures, pelleted by centrifugation, and resuspended in 100 µl of 1x binding buffer (10 mM HEPES (pH 7.4), 140 mM NaCl, and 2.5 mM CaCl2) and stained with 5 µl of annexin V-PE (BD PharMingen) for 15 min at room temperature in the dark. Cells were diluted in 1x binding buffer and analyzed on a FACScan flow cytometer (BD Biosciences).
Immunoblot analysis
Immunoblots were performed as previously described using Bcl-xL-, Bcl-2-, or Hsp90-specific Ab (Santa Cruz Biotechnology, Santa Cruz, CA) diluted 1/1000 in blocking buffer (6). Changes in protein levels relative to Hsp90 were determined by densitometry using NIH Image 1.62 software.
RNase protection assay
Total RNA was isolated using TRIzol RNA isolation reagent (Invitrogen, San Diego, CA). RNase protection assays were performed according to the manufacturer’s instructions using a RiboQuant RNase protection kit, 5 µg of total RNA per sample, and the mouse AP0-2 probe set (BD PharMingen). The resulting gel was dried and developed by autoradiography. Changes in mRNA levels relative to L32 and GAPDH were determined by densitometry using NIH Image 1.62 software.
Retroviral transduction of B cells
The GFP-RV bicistronic vector was obtained from K. Murphy (St. Louis, MO) (7) and the Phoenix-Eco packaging cell line was obtained from G. Nolan (Stanford, CA) (8). The murine Bcl-xL cDNA was cloned into GFP-RV (6). The human Bcl-2 cDNA cloned into MSCV-I-GFP was kindly provided by S. Korsmeyer (Boston, MA) (9). Transfection of the packaging cell line was performed using Effectene (Qiagen, Valencia, CA), and viral supernatants were harvested 48–72 h later. Anti-CD40 Ab (5 µg/ml) and LPS-activated (10 µg/ml; 24 h) purified splenic B cells were retrovirally transduced by incubation of 1 x 107 B cells at 1 x 106/ml with an equal volume of viral supernatant and 2 µg/ml polybrene. The cultures were centrifuged at 500 x g for 1 h at room temperature. The culture medium was changed after 24 h. Green fluorescent protein (GFP)-positive cells were sorted by FACS (BD Biosciences) 36 h after transduction and cultured in the presence or absence of IL-21 (200 ng/ml) for 24 h. Cells were subsequently analyzed for apoptosis by propidium iodide analysis.
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Results |
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To initially identify any differences between murine and human B cell responses to IL-21, we examined the ability of IL-21 to costimulate B cell proliferation. Splenic B cells from wild-type and IL-21R-/- mice were purified and cultured with graded doses of IL-21 (0–200 ng/ml) in the presence of anti-CD40 Ab or anti-IgM Ab and IL-4. In contrast to that seen with human IL-21, murine IL-21 did not enhance the proliferation of anti-CD40 Ab-costimulated wild-type B cells (Fig. 1A). However, similar to human IL-21, murine IL-21 did inhibit anti-IgM Ab- and IL-4-mediated proliferation of wild-type B cells in a dose-dependent manner (Fig. 1B). The IL-21R-/- B cells were not susceptible to the antiproliferative effects of IL-21.
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Considering that murine IL-21 does not costimulate the proliferation of B cells, it is possible that IL-21 could instead be inducing death. To determine what effect IL-21 has on the viability of primary murine B cells, splenic B cells from wild-type and IL-21R-/- mice were purified and cultured in the presence or absence of IL-21 for 24 h. Subsequently, the cultures were analyzed for the presence of apoptotic cells by propidium iodide analysis. As expected, a significant proportion of the population of untreated cells was found to be subdiploid. However, the addition of IL-21 to wild-type B cell cultures yielded a 2-fold increase in the number of apoptotic cells (Fig. 2A). In contrast, there was no difference in the percentage of apoptotic cells between untreated and IL-21-treated cultures of IL-21R-/- B cells indicating the specific requirement of this receptor in order for IL-21 to transduce an apoptotic signal. In addition to inducing apoptosis in resting B cells, IL-21 treatment also induced the apoptosis of anti-CD40 Ab-activated B cells (Fig. 2B). Wild-type B cells cultured in the presence of IL-21 for 24 h after activation had a 5-fold increase in the number of subdiploid cells compared with anti-CD40 Ab alone. Interestingly, IL-21 treatment of anti-CD40 Ab-activated wild-type B cells also induces a 3-fold increase in the number of cells transitioning from the G1/G0 phase to S phase of the cell cycle (-IL-21: 6.2% ± 0.89%; +IL-21: 19.4% ± 3.9%). The dual effects of IL-21 on anti-CD40 Ab-activated B cells may explain why IL-21 does not inhibit anti-CD40 Ab-mediated proliferation even though it induces apoptosis in these cells.
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In an effort to determine the mechanism underlying the apoptotic effects of IL-21 signaling, we examined whether IL-21 affects the expression of various members of the Bcl-2 family. The Bcl-2 family is a group of mitochondrial membrane proteins composed of both pro- and antiapoptotic members that can suppress or promote mitochondrial dysfunction. It is the relative intracellular levels of these pro- and antiapoptotic proteins that can determine whether or not apoptosis is activated or suppressed (10, 11). RNase protection assays showed that, within 3 h of IL-21 treatment, several of the antiapoptotic Bcl-2 members are down-regulated in both resting B cells and in B cells preactivated with anti-CD40 Ab for 24 h (Fig. 4A). In both resting and activated B cells, Bcl-2 mRNA levels were most dramatically decreased upon IL-21 stimulation, representing a 7-fold reduction to essentially nondetectable levels of mRNA, whereas Bcl-xL mRNA levels were down-regulated 
2-fold. These results were confirmed by quantitative real-time PCR (data not shown). In addition, the mRNA levels of Bfl-1 and Bcl-w, also antiapoptotic factors, were reduced 2-fold with IL-21 treatment in resting B cells. Within 6 h of IL-21 stimulation of primary B cells, both Bcl-2 and Bcl-xL protein levels were significantly decreased (Fig. 4B), which correlates with the onset of apoptosis as determined by annexin V staining (Fig. 3A). These experiments show that, in primary B cells, IL-21 signaling instructs the rapid repression of multiple antiapoptotic factors allowing for the activation of cell death.
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The studies in the previous section suggest that IL-21 signaling results in the repression of Bcl-xL and Bcl-2 expression and subsequently cell death. To determine whether overexpression of Bcl-xL or Bcl-2 could prevent IL-21-induced apoptosis, we used a retroviral gene expression system to overexpress these prosurvival factors in primary B cells. Bcl-xL or Bcl-2 cDNA were cloned into a bicistronic retroviral expression construct that allows for the coexpression of the antiapoptotic factor and GFP within the same cell. Purified wild-type B cells were first activated with LPS and anti-CD40 Ab for 24 h, and then transduced with retrovirus containing either the empty GFP vector or the vector including the antiapoptotic factor and GFP. GFP-positive cells were sorted by flow cytometry to 95% purity and then cultured in the presence or absence of IL-21 for 24 h. The presence of apoptotic cells was detected by propidium iodide analysis. B cells transduced with GFP alone resulted in a 2- to 3-fold increase in apoptotic cells after stimulation with IL-21 (Fig. 5). However, when Bcl-xL or Bcl-2 was coexpressed with GFP, there was no difference in the percentage of apoptotic cells between cultures with or without IL-21. These data indicate that either Bcl-xL or Bcl-2 overexpression is sufficient to rescue primary B cells from IL-21-induced apoptosis, providing additional evidence that the apoptotic effect of IL-21 is mediated through the down-regulation of these prosurvival proteins.
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To further explore the capacity of IL-21 to induce the apoptosis of B cells, we asked whether or not other known B cell costimulatory factors such as IL-4, LPS, and anti-CD40 Ab, or B cell receptor (BCR) activation could inhibit IL-21-induced apoptosis. Primary resting B cells were cultured in the presence of IL-21 and either IL-4, LPS, anti-CD40 Ab, or anti-IgM Ab for 24 h. B cells were also pretreated with IL-4, LPS, anti-CD40 Ab, or anti-IgM Ab for 6 h followed by the addition of IL-21 for 24 h. Subsequently, the cultures were analyzed for the presence of apoptotic cells by propidium iodide analysis.
Although BCR activation of resting B cells results in the induction of apoptosis, the addition of IL-21 to these cultures did not result in an increase in the percentage of apoptotic cells (Fig. 6A). The lack of an additive effect in the presence of IL-21 suggests either that the apoptotic programs induced by IL-21 and anti-IgM Ab stimulation overlap or that the maximum susceptibility of B cells to apoptosis has already been reached by each individual stimulus.
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Pretreatment of primary B cells with anti-CD40 Ab up-regulates Bcl-xL expression resulting in protection from IL-21-induced apoptosis
We have shown that the pretreatment of primary resting B cells with anti-CD40 Ab for 6 h is sufficient to protect these cells from IL-21-induced apoptosis (Fig. 6D). However, the simultaneous culturing of B cells with anti-CD40 Ab and IL-21 does not provide protection from apoptosis. Additionally, we have also shown that a longer activation of B cells with anti-CD40 Ab (24–36 h) does not alter the susceptibility of these cells to IL-21-induced apoptosis (Fig. 2B). To determine the minimal time of anti-CD40 Ab pretreatment required for maximal protection from IL-21-induced apoptosis, we conducted a time course of pretreatment of splenic B cells with anti-CD40 Ab for 0–6 h before the introduction of IL-21 for an additional 24 h and then analyzed for apoptosis by propidium iodide staining. We found that the percentage of apoptotic B cells induced by IL-21 linearly decreases with the increasing length of time of anti-CD40 Ab pretreatment, and that 6 h of anti-CD40 Ab pretreatment was required for maximal protection (Fig. 7A).
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Discussion |
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We also examined the effects of various costimuli on IL-21-mediated apoptosis of B cells and found that, whereas anti-IgM Ab treatment of B cells induces apoptosis, the addition of IL-21 to anti-IgM Ab-stimulated cultures did not result in an increase in the percentage of apoptotic cells. Moreover, prosurvival costimulatory factors such as IL-4, LPS, and anti-CD40 Ab could not prevent IL-21-mediated apoptosis. Only when B cells were pretreated with anti-CD40 Ab for 6 h before IL-21 stimulation, could CD40 activation prevent apoptosis. Interestingly, B cells subjected to longer pretreatments (24 h) with anti-CD40 Ab were no longer protected from IL-21-induced apoptosis. Perhaps the disparity in protection offered by anti-CD40 Ab stimulation is due to the induction of a prosurvival factor that is transiently increased only in the initial hours of anti-CD40 Ab activation. Alternatively, this prosurvival factor could be repressed or lack stability in late anti-CD40 Ab-activated B cells.
Apoptosis plays a critical role in B cell development and homeostasis and is tightly regulated by many cytokines. IL-4 is a potent antiapoptotic cytokine for B cells that can prevent death induced by Ig cross-linking, glucocorticoids, Fas ligation, and the withdrawal of growth factors from culture (13, 14, 15, 16). It has been shown that the antiapoptotic activity of IL-4 in B cells is in part mediated by the induced expression of Bcl-xL, a member of the Bcl-2 family (6, 17).
Although IL-4 is a cytokine that promotes B cell viability, there are also cytokines, such as TNF-, TGF, and IFN-, that promote B cell death. TNF- induces cell death via the activation of caspase-8 (18, 19). The overexpression of Bcl-2, Bcl-xL, and Bfl-1 has been shown to inhibit TNF--mediated apoptosis (20, 21, 22, 23, 24). TGF is another cytokine that has been shown to promote apoptosis in resting human B cells, in the murine lymphoma WEHI 231, and in the human B cell lymphoma Ramos (25, 26, 27). TGF-mediated apoptosis of Ramos cells has been associated with the down-regulation of Bcl-xL expression (28). In addition, studies have shown that IFN- also induces the apoptosis of the immature B cell line WEHI 279 and normal murine pre-B cells via the down-regulation of Bcl-2 and Bcl-xL (29). Although the receptors and ensuing signaling cascades for these cytokines are very different, the modulation of Bcl-2 family members appears to be an important common mechanism in determining cell survival.
Like these cytokines, we have demonstrated that IL-21 also promotes the apoptosis of B cells by down-regulating the antiapoptotic molecules Bcl-2 and Bcl-xL. Most interestingly, IL-21 is structurally homologous to IL-4, IL-2, and IL-15, which all belong to the class 1 receptor cytokine family and utilize the c to transduce signals. The ability of IL-21 to directly induce apoptosis is a highly unusual and novel property of a cytokine that signals through the c, considering that this class of cytokines is usually known to induce proliferation and mediate prosurvival effects.
During an immune response, there is a balance between signaling pathways that support cell survival and proliferation and those that culminate in apoptosis to maintain homeostasis of the immune system and prevent the development of autoimmunity. IFN- is an important mediator of the Th1 response, which negatively regulates B cell differentiation and proliferation, whereas IL-4, a Th2 cytokine, has been shown to promote B cell proliferation and confer resistance to apoptosis. Interestingly, we have recently demonstrated that IL-21 is preferentially produced by Th2 cells (30). The IL-21-mediated apoptosis of B cells may represent a novel mechanism of cell death regulated by the Th2 response. It is possible that IL-21 is necessary to control any excessive B cell proliferation and Ab production promoted during a Th2 immune response to maintain homeostasis. In support of this notion, the initial characterization of IL-21R-/- mice revealed 3-fold higher levels of serum IgE as compared with those of wild-type mice (4). These data suggest that IL-21 does play a role in regulating B cell responses in vivo, possibly by regulating the survival of Ab-producing B cells.
Our studies show that IL-21 can induce death in normal primary B cells. However, a recent study demonstrated that human IL-21 induced the proliferation and inhibited apoptosis of three of the six human myeloma cell lines tested (5). One possibility is that murine IL-21 has divergent biological effects from the human cytokine. Another explanation for contrasting results is the difference in differentiation status between the myeloma cells, a plasma cell stage, and the primary mature B cells studied here. A last possibility is that the pathophysiological nature of these myeloma cells renders them insensitive to the apoptotic signaling induced by IL-21, possibly through aberrant receptor signaling or the constitutive up-regulation of antiapoptotic factors. TNF-, another apoptosis-inducing cytokine, also stimulates the proliferation of the same human myeloma cell lines used in this study (5). Interestingly, prior experiments have demonstrated that IL-21 costimulates human B cell proliferation under specific conditions (2). However, our studies show that IL-21 does not costimulate primary murine B cell proliferation (Fig. 1). Taken together, it is possible that IL-21 stimulation could potentially transduce both a proliferative and apoptotic signal, and depending on the status of the cell, there may be variable results in cell viability. It will be interesting to determine whether murine IL-21 induces or inhibits the apoptosis of murine myeloma cell lines.
In conclusion, we have demonstrated that IL-21 induces apoptosis in both resting and activated primary murine B cells, which is correlated with the reduced expression of Bcl-xL and Bcl-2. The IL-21-mediated apoptosis of B cells can be prevented by the reconstitution of Bcl-xL or Bcl-2 expression by either overexpressing these proteins or inducing their expression and accumulation by preactivating the B cells appropriately before IL-21 stimulation. Taken together, these data demonstrate that the apoptotic effect induced by IL-21 is mediated by the down-regulation of the antiapoptotic proteins Bcl-xL and Bcl-2, revealing a novel apoptotic pathway, transduced by the IL-21R, for B lymphocytes. Dysregulation of this pathway could lead to a lack of B cell homeostasis and have implications in diseases such as multiple myeloma.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael J. Grusby, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115. E-mail address: mgrusby{at}hsph.harvard.edu
3 Abbreviations used in this paper: c, common chain; GFP, green fluorescent protein; BCR, B cell receptor; Boc-D(OMe)-FMK, Boc-Asp(OME)-fluoromethyl ketone.
Received for publication November 20, 2002. Accepted for publication February 7, 2003.
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E. Bolesta, A. Kowalczyk, A. Wierzbicki, C. Eppolito, Y. Kaneko, M. Takiguchi, L. Stamatatos, P. A. Shrikant, and D. Kozbor Increased Level and Longevity of Protective Immune Responses Induced by DNA Vaccine Expressing the HIV-1 Env Glycoprotein when Combined with IL-21 and IL-15 Gene Delivery J. Immunol., July 1, 2006; 177(1): 177 - 191. [Abstract] [Full Text] [PDF]
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M. Strengell, A. Lehtonen, S. Matikainen, and I. Julkunen IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells J. Leukoc. Biol., June 1, 2006; 79(6): 1279 - 1285. [Abstract] [Full Text] [PDF]
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D. de Totero, R. Meazza, S. Zupo, G. Cutrona, S. Matis, M. Colombo, E. Balleari, I. Pierri, M. Fabbi, M. Capaia, et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells Blood, May 1, 2006; 107(9): 3708 - 3715. [Abstract] [Full Text] [PDF]
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B. R. Herrin and L. B. Justement Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells J. Immunol., April 1, 2006; 176(7): 4163 - 4172. [Abstract] [Full Text] [PDF]
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R. Ettinger, G. P. Sims, A.-M. Fairhurst, R. Robbins, Y. S. da Silva, R. Spolski, W. J. Leonard, and P. E. Lipsky IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells J. Immunol., December 15, 2005; 175(12): 7867 - 7879. [Abstract] [Full Text] [PDF]
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 Z. Wu, H.-P. Kim, H.-H. Xue, H. Liu, K. Zhao, and W. J. Leonard Interleukin-21 Receptor Gene Induction in Human T Cells Is Mediated by T-Cell Receptor-Induced Sp1 Activity Mol. Cell. Biol., November 15, 2005; 25(22): 9741 - 9752. [Abstract] [Full Text] [PDF]
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 H.-P. Kim, L. L. Korn, A. M. Gamero, and W. J. Leonard Calcium-dependent Activation of Interleukin-21 Gene Expression in T Cells J. Biol. Chem., July 1, 2005; 280(26): 25291 - 25297. [Abstract] [Full Text] [PDF]
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K. Ozaki, R. Spolski, R. Ettinger, H.-P. Kim, G. Wang, C.-F. Qi, P. Hwu, D. J. Shaffer, S. Akilesh, D. C. Roopenian, et al. Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-6 J. Immunol., November 1, 2004; 173(9): 5361 - 5371. [Abstract] [Full Text] [PDF]
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M. Strengell, I. Julkunen, and S. Matikainen IFN-{alpha} regulates IL-21 and IL-21R expression in human NK and T cells J. Leukoc. Biol., August 1, 2004; 76(2): 416 - 422. [Abstract] [Full Text] [PDF]
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H. Jin, R. Carrio, A. Yu, and T. R. Malek Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis J. Immunol., July 1, 2004; 173(1): 657 - 665. [Abstract] [Full Text] [PDF]
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 G. Wang, M. Tschoi, R. Spolski, Y. Lou, K. Ozaki, C. Feng, G. Kim, W. J. Leonard, and P. Hwu In Vivo Antitumor Activity of Interleukin 21 Mediated by Natural Killer Cells Cancer Res., December 15, 2003; 63(24): 9016 - 9022. [Abstract] [Full Text] [PDF]
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