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The Journal of Immunology, 2001, 167: 1-5.
Copyright © 2001 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: The Common {gamma}-Chain Is an Indispensable Subunit of the IL-21 Receptor Complex1

Hironobu Asao2,*, Chikara Okuyama*,{dagger}, Satoru Kumaki{dagger}, Naoto Ishii*, Shigeru Tsuchiya{dagger}, Don Foster{ddagger} and Kazuo Sugamura*,§

* Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan; {dagger} Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; {ddagger} Department of Functional Cloning, ZymoGenetics, Seattle, WA 98102; and § Core Research for Evolutional Science and Technology of the Japan Science and Technology Corporation, Tokyo, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The common {gamma}-chain ({gamma}c) is an indispensable subunit of the functional receptor complexes for IL-4, IL-7, IL-9, and IL-15 as well as IL-2. Here we show that the {gamma}c is also shared with the IL-21R complex. Although IL-21 binds to the IL-21R expressed on {gamma}c-deficient ED40515- cells, IL-21 is unable to transduce any intracytoplasmic signals. However, in ED{gamma}-16 cells, a {gamma}c-transfected ED40515- cell line, IL-21 binds to the IL-21R and can activate Janus kinase (JAK)1, JAK3, STAT1, and STAT3. The chemical cross-linking study reveals the direct binding of IL-21 to the {gamma}c. These data clearly demonstrate that the {gamma}c is an indispensable subunit of the functional IL-21R complex.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The most unique feature of the cytokine receptor family is their ability for sharing with many cytokines. The common {beta}-chain, which was originally identified as a GM-CSF receptor {beta}-chain, is shared with IL-3 and IL-5 (1). Glycoprotein 130, which was originally discovered as a component of the IL-6R complex, is shared with IL-11, oncostatin M, LIF, ciliary neurotrophic factor, and cardiotrophin-1 (2). We previously reported the cloning of an IL-2R {gamma}-chain and demonstrated it to be an essential component for the functional IL-2R complex (3, 4). The IL-2R {gamma}-chain was later uncovered to be an indispensable subunit of the IL-4, IL-7, IL-9, and IL-15 receptors and is now referred to as the common {gamma}-chain ({gamma}c)3 (5). The human {gamma}c gene is located on the X chromosome, and patients with X-linked SCID (XSCID), a disease characterized by an absence of T and NK cells with a presence of nonfunctional B cells, have mutations in the {gamma}c gene (6, 7). The mutant {gamma}cs detected in the XSCID patients were revealed to have no ability for formation of the functional receptor complexes (8). Furthermore, {gamma}c gene-targeting mice demonstrated that various phenotypes of XSCID patients are caused by the dysfunction of the {gamma}c (9, 10, 11). These findings raised the next question of which cytokines are responsible for each hemopoietic cell development disturbed in XSCID patients. Gene disruption of either IL-7 or the IL-7R {alpha}-chain led to severe developmental defects of T and B cells (12, 13). Therefore, IL-7 was thought to be an essential cytokine for T and B cell differentiation and proliferation in mice. Gene disruption of the IL-2R {beta}-chain as well as the {gamma}c but not of IL-2, led to a defect of NK cell development (14, 15). Because the IL-15R complex is composed of the IL-2R {beta}-chain and the {gamma}c in addition to the unique IL-15R {alpha}-chain, dysfunction of IL-15 seems to lead to a severe defect of NK cells (16, 17). However, the functional roles of the {gamma}c are still not fully understood.

Recently a novel cytokine, IL-21 and its receptor were identified (18, 19). Interestingly, structural similarities between IL-21 and IL-2, IL-4, and IL-15 and between the IL-21R and the IL-2R {beta}-chain and the IL-4R {alpha}-chain are shown. These findings led us to speculate that IL-21 also shares the {gamma}c as a functional subunit of its IL-21R complex. In this paper we clearly demonstrate that the {gamma}c is an indispensable component of the functional IL-21R as well as receptors for IL-2, IL-4, IL-7, IL-9, and IL-15.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cells and Abs

Cells used in this paper were of the human T cell leukemia virus-I-transformed human T cell line ED40515- (20), which lacks expression of {gamma}c, and ED40515--derived transfectants, ED{gamma}-15, ED{gamma}-16, EDtSH{gamma}-4, and ED-AV-7R.cl2 as reported previously (8, 21, 22). ED{gamma}-15 and ED{gamma}-16 cells express wild-type human {gamma}c. EDtSH{gamma}-4 and ED-AV-7R.cl2 cells express a mutant {gamma}c deleted of C-terminal 50 aa and a mutant {gamma}c with one amino acid substitution at the extracellular region (from Ala156 to Val), respectively; both of them were derived from XSCID patients. These cell lines were maintained in RPMI 1640 medium supplemented with 10% FBS, 2 mM L-glutamine, penicillin, and streptomycin.

An anti-human IL-2R {gamma}-chain mAb (TUGh4) was described previously (23). Anti-Janus kinase (JAK)1, -JAK2, -JAK3, -Tyk2, -STAT1, -STAT3, and -STAT5 polyclonal Abs were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Phosphospecific polyclonal Abs, anti-phospho-STAT1 (Y701), -STAT3 (Y705), and -STAT5 (Y694), and P-Tyr-100, which is an anti-phosphotyrosine monoclonal Ab, were purchased from Cell Signaling Technology (Beverly, MA). HRP-labeled anti-mouse IgG and HRP-labeled anti-rabbit IgG Abs used as secondary Abs were purchased from KPL (Gaithersburg, MD).

Immunofluorescence staining and binding of IL-21 to ED40515- and ED{gamma}-16 cells

Immunofluorescence staining of cells with biotin-conjugated TUGh4 was conducted as described previously (8). Recombinant human IL-21 was conjugated to N-hydroxysulfosuccinimide-long chain-biotin (Pierce, Rockford, IL). Cells were incubated with 100 ng/ml biotin-conjugated IL-21 for 60 min at 4°C. After washing, the cells were incubated with streptavidin-PE (BD Biosciences, San Jose, CA) for 20 min at 4°C to be visualized. The cells were then subjected to a flow cytometer (FACSCalibur; BD Immunocytometry Systems, Mountain View, CA). Incubation with 2 µg/ml unlabeled IL-21 before the addition of the biotinylated IL-21 provided the background control staining.

Immunoprecipitation and immunoblot assay

Immunoprecipitation and immunoblot assay were described previously (22, 24). Cells were stimulated with 10 ng/ml IL-21 or 1 nM IL-2 for 10 min for immunoprecipitation of the JAKs and for 30 and 60 min for phosphospecific immunoblot assay of the STATs.

EMSA

EMSA was conducted as described previously (24). Double-stranded 32P-labeled M67-SIE sequence (5'-GTGCATTTCCCGTAAATCTTGTCTACAATTC-3') and {beta}-casein-SIE sequence (5'-TGTGGACTTCTTGGAAT TAAGGGACTTTTG-3') were used as probes for STAT1/3 and STAT5, respectively.

Cross-linking experiment

Cells were incubated with 100 ng/ml of biotinylated IL-21 or IL-2 for 1 h on ice. Cells were washed with ice-cold PBS and then suspended in ice-cold cross-linking buffer (1 mM MgCl2-PBS pH 8.3). Disuccinimidyl suberate (DSS; Pierce) was added at a concentration of 100 µg/ml followed by another 30-min incubation on ice. Cells were harvested and lysed for immunoprecipitation as described above. HRP-conjugated streptavidin (Amersham Pharmacia Biotech, Little Chalfont, U.K.) was used for the detection of biotinylated IL-21 or IL-2.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
IL-21 binds to ED40515- cell line negative for {gamma}c

To investigate the possible involvement of {gamma}c in formation of the IL-21R complex, we first tested IL-21R expression on the ED40515- cell line, which is reportedly defective for {gamma}c expression on cell surfaces (20). We conducted flow cytometry on this cell line using biotinylated human IL-21. ED40515- cells and also ED{gamma}-16 cells, which stably express the exogenous wild-type {gamma}c, bind IL-21 (Fig. 1Go, bottom). The specificity of biotinylated IL-21 binding to its receptor was controlled by a blocking experiment with an excess of unlabeled IL-21. These results suggested that IL-21 can bind to its receptor without {gamma}c. RT-PCR showed the expression of IL-21R mRNA in the ED40515- cell line (data not shown). The expression of {gamma}c on each cell line is shown (Fig. 1Go, top).



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  		FIGURE 1. Binding of IL-21 to ED40515- and ED{gamma}-16 cells. Cells were incubated with 10 µg/ml biotin-conjugated TUGh4 (anti-human {gamma}c mAb) (top, thick lines) or 100 ng/ml biotin-conjugated IL-21 (bottom, thick lines) followed by streptavidin-PE and subjected to flow cytometric analysis. Thin lines represent control staining of biotinylated TUGh4 in the presence of 300 µg/ml unlabeled TUGh4 (top) or control staining of biotinylated IL-21 in the presence of 2 µg/ml unlabeled IL-21 (bottom).

 
IL-21 activates JAK1 and JAK3 in the presence of {gamma}c

Next, we examined whether IL-21 requires {gamma}c for its intracellular signal transduction. All the cytokines whose receptors belong to the cytokine receptor family induce activation of JAKs with various combinations among the JAK family tyrosine kinases. The IL-21R and the {gamma}c were reported to associate with JAK1 and JAK3, respectively (19, 21, 25, 26, 27). Hence, we examined tyrosine phosphorylation of the JAKs as a result of their activation. We immunoprecipitated JAK1, JAK2, JAK3, and Tyk2 before and after IL-21 or IL-2 stimulation and then immunoblotted with P-Tyr-100. IL-21 as well as IL-2 apparently induced phosphorylation of JAK1 in ED{gamma}-16 cells but not in ED40515- cells (Fig. 2GoA). Phosphorylation of JAK3 was detectable in these cell lines even before stimulation, and was significantly enhanced in ED{gamma}-16 cells after stimulation with either IL-21 or IL-2 (Fig. 2GoB). Similar results were obtained in ED{gamma}-15, which is another cell line expressing the exogenous wild-type {gamma}c (data not shown). These data clearly demonstrate that IL-21 absolutely requires the {gamma}c for its signal transduction. The constitutive tyrosine phosphorylation of JAK3 was previously reported with other human T cell leukemia virus-I-infected cell lines (28). Phosphorylation of Tyk2 was undetectable, and we detected weak phosphorylation of JAK2 in ED{gamma}-16 cells upon stimulation with either IL-21 or IL-2. Because the expression level of JAK2 was quite low, the weak bands may reflect physiologically significant activation of JAK2.



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  		FIGURE 2. IL-21 induces JAK1 and JAK3 activation only in the presence of {gamma}c. ED40515- and ED{gamma}-16 cells were stimulated with either IL-2 or IL-21 as indicated for 10 min. The cell lysates were immunoprecipitated with anti-JAK1, anti-JAK2 (A), anti-JAK3, or anti-Tyk2 (B) Abs. Phosphotyrosine was detected by P-Tyr-100 (top). The filters were reprobed with the anti-JAK1, -JAK2, -JAK3, or -Tyk2 Ab, respectively, to determine the amount of JAKs in each lane (bottom). The positions of each JAK are indicated as arrows.

 
IL-21 induced activation of STATs in ED{gamma}-16 cells but not in ED40515- cells

STATs are also phosphorylated and activated for their transcriptional activities upon cytokine stimulation (29). Hence, we examined IL-21-mediated phosphorylation of STAT1, STAT3, and STAT5 with ED{gamma}-16 and ED40515- cells. The cells were stimulated with IL-21, and their extracts were then immunoblotted with Abs specific for tyrosine-phosphorylated STAT1, STAT3, and STAT5. IL-21 as well as IL-2 clearly induced tyrosine phosphorylation of STAT1 in ED{gamma}-16 cells but not in ED40515- cells (Fig. 3GoA). Phosphorylation of STAT3 was detectable in these cell lines even before stimulation, and was significantly enhanced in ED{gamma}-16 cells after stimulation with either IL-21 or IL-2 (Fig. 3GoB). Although IL-2 induced significant tyrosine phosphorylation of STAT5, IL-21 produced a weak phosphorylation of STAT5 (Fig. 3GoC). A high concentration of IL-21 (100 ng/ml) was not able to enhance the phosphorylation of STAT5 (data not shown). To confirm these results, we conducted EMSA with the ED{gamma}-16 cell extracts. Both IL-2 and IL-21 activated STAT1 activity. The DNA binding activity of STAT3 was observed without stimulation; however, upon IL-2 AND IL-21 stimulation, the binding activity was increased (Fig. 3GoD). Whereas IL-2 activated STAT5, IL-21 induced a weak activation of STAT5. The specificity of the bands for the STATs was verified with supershift assays using specific Abs. In the presence of anti-STAT1, -STAT3, or -STAT5, the bands almost disappeared, respectively, and formed supershifted bands in the cases of anti-STAT3 and -STAT5. These results were consistent with those of immunoblots using phosphotyrosine-specific Abs. Homodimerization of the IL-21R is reported to activate STAT5 but not STAT3 (19). This observation seems inconsistent with our present results. Although the IL-21R was reported to have a consensus motif for STAT3 binding in its C-terminal tail (18), it is not clear which tyrosine residue is responsible for the activation of STAT5. Further study will need to identify critical regions for the activation of each STAT.



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  		FIGURE 3. STAT activation with IL-21 in wild-type or mutant {gamma}c-expressing cells. ED40515-, ED{gamma}-16, EDtSH{gamma}-4, and ED-AV-7R.cl2 were stimulated with either IL-2 or IL-21 as indicated. Tyrosine-phosphorylated STATs were detected with anti-phospho STAT1 (pY701) (A), anti-phospho STAT3 (pY705) (B), and anti-phospho STAT5 (pY694) (C) Abs (top). These filters were reprobed with anti-STAT1, -STAT3, and -STAT5 Abs, respectively, to determine the amount of STAT in each lane (bottom). The positions of each STAT are indicated as arrows. Whole cell extracts of ED{gamma}-16 cells stimulated with either IL-2 or IL-21 were incubated with 32P-labeled M67-SIE probe (D, lanes 1–9) or 32P-labeled {beta}-casein-SIE probe (D, lanes 10–15) in the presence or absence of anti-STAT Abs as indicated. Supershifted bands are indicated by * for STAT3 or ** for STAT5. Nonspecific bands are indicated by arrows.

 
Next we tested {gamma}c mutants for their signal-transducing activities as a component of the IL-21R complex. We used tSH and AV mutants of the {gamma}c, which were derived from XSCID patients whose phenotypes were a typical and a NK-positive atypical XSCID, respectively (8, 22). tSH mutant lacks C-terminal 50 aa with a result of frame shift mutation, and we reported previously that tSH mutant had no function on IL-2-induced signal transduction (8). As expected, tSH mutant also had no function on IL-21-induced STAT activation. In contrast, AV mutant has an amino acid substitution, Ala156 to Val on the extracellular domain of {gamma}c (8). We reported that AV mutant expressing ED40515- subline, ED-AV-7R.cl2, was selectively impaired in their responses to IL-4 or IL-7, although responses to IL-2 or IL-15 were relatively maintained (22). IL-21-induced STAT3 activation through AV mutant {gamma}c was comparable with wild-type {gamma}c, however, activation of STAT1 was impaired. These results suggest that IL-21 as well as IL-2 require both of the extracellular and intracytoplasmic regions of the {gamma}c for the signal transduction.

Sharing of the {gamma}c with the IL-21R complex

IL-21 was revealed to bind to ED40515- cells negative for {gamma}c expression (Fig. 1Go), suggesting the dispensability of the {gamma}c for IL-21 binding. However, because the {gamma}c was found to be required for the IL-21 signaling, we speculated that the {gamma}c is an effector subunit of the IL-21R complex. To examine this possibility, we attempted to detect IL-21 in the {gamma}c receptor complex. ED40515- and ED{gamma}-16 cells were incubated with biotinylated IL-21 or biotinylated IL-2 and cross-linked with a chemical cross-linker (DSS). Their lysates were immunoprecipitated with anti-{gamma}c mAb (TUGh4). The immunoprecipitates were then separated with SDS-PAGE and transferred to a membrane, followed by detection with HRP-labeled-streptavidin. Fig. 4Go shows biotinylated-IL-21-{gamma}c complex ~85 kDa in ED{gamma}-16 cells but not in ED40515- cells. This molecular size is comparable with that of {gamma}c (64–70 kDa) plus IL-21 (15 kDa). Similar results were obtained with biotinylated IL-2. These results suggest that the IL-21R complex contains the {gamma}c as an essential component like the IL-2R complex. In this paper, we clearly demonstrated that {gamma}c is an indispensable receptor subunit for IL-21 as well as IL-2, IL-4, IL-7, IL-9, and IL-15.



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  		FIGURE 4. Sharing of the {gamma}c with the IL-21R complex. ED40515- and ED{gamma}-16 cells were incubated with either biotinylated IL-2 or IL-21, respectively, for 1 h on ice. These ligands were chemically cross-linked to the receptors with DSS as described in Materials and Methods. The cell lysates were immunoprecipitated with ({gamma}) or without (C) anti-{gamma}c Ab. Biotinylated-IL-2 or IL-21-associated {gamma}c was detected with HRP-conjugated streptavidin. The position of biotinylated IL-2- or IL-21-associated {gamma}c is indicated by the arrow.

 


   Acknowledgments
 
We thank Dr. Lishomwa C. Ndhlovu for critical review of the manuscript.


   Footnotes
 
1 This work was supported in part by a grant for Core Research for Evolutional Science and Technology of the Japan Science and Technology Corporation, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, and a grant-in-aid for scientific research on priority areas from the Ministry of Education, Science, Sport, and Culture of Japan. Back

2 Address correspondence and reprint requests to Dr. Hironobu Asao, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 Japan. E-mail address: asao-h{at}mail.cc.tohoku.ac.jp Back

3 Abbreviations used in this paper: {gamma}c, common {gamma}-chain; JAK, Janus kinase; XSCID, X-linked SCID; DSS, disuccinimidyl suberate. Back

Received for publication March 27, 2001. Accepted for publication May 3, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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F. A. Scheeren, S. A. Diehl, L. A. Smit, T. Beaumont, M. Naspetti, R. J. Bende, B. Blom, K. Karube, K. Ohshima, C. J. M. van Noesel, et al.
IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis
Blood, May 1, 2008; 111(9): 4706 - 4715.
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A H Sawalha, K M Kaufman, J A Kelly, A J Adler, T Aberle, J Kilpatrick, E K Wakeland, Q-Z Li, A E Wandstrat, D R Karp, et al.
Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus
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F. Caprioli, M. Sarra, R. Caruso, C. Stolfi, D. Fina, G. Sica, T. T. MacDonald, F. Pallone, and G. Monteleone
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J. Immunol., February 1, 2008; 180(3): 1800 - 1807.
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D. de Totero, R. Meazza, M. Capaia, M. Fabbi, B. Azzarone, E. Balleari, M. Gobbi, G. Cutrona, M. Ferrarini, and S. Ferrini
The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways
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Y. Li and C. Yee
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I. D. Davis, K. Skak, M. J. Smyth, P. E.G. Kristjansen, D. M. Miller, and P. V. Sivakumar
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S. Liu, G. Lizee, Y. Lou, C. Liu, W. W. Overwijk, G. Wang, and P. Hwu
IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells
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T. Onoda, M. Rahman, H. Nara, A. Araki, K. Makabe, K. Tsumoto, I. Kumagai, T. Kudo, N. Ishii, N. Tanaka, et al.
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B. R. Barker, J. G. Parvani, D. Meyer, A. S. Hey, K. Skak, and N. L. Letvin
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K. A. Casey and M. F. Mescher
IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype
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I. D. Davis, B. K. Skrumsager, J. Cebon, T. Nicholaou, J. W. Barlow, N. P. H. Moller, K. Skak, D. Lundsgaard, K. S. Frederiksen, P. Thygesen, et al.
An Open-Label, Two-Arm, Phase I Trial of Recombinant Human Interleukin-21 in Patients with Metastatic Melanoma
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R. Zeng, R. Spolski, E. Casas, W. Zhu, D. E. Levy, and W. J. Leonard
The molecular basis of IL-21-mediated proliferation
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L. White, S. Krishnan, N. Strbo, H. Liu, M. A. Kolber, M. G. Lichtenheld, R. N. Pahwa, and S. Pahwa
Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)
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J. M. Coquet, K. Kyparissoudis, D. G. Pellicci, G. Besra, S. P. Berzins, M. J. Smyth, and D. I. Godfrey
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A. Frohlich, B. J. Marsland, I. Sonderegger, M. Kurrer, M. R. Hodge, N. L. Harris, and M. Kopf
IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo
Blood, March 1, 2007; 109(5): 2023 - 2031.
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K. L. Good, V. L. Bryant, and S. G. Tangye
Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21
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A. Suto, A. L. Wurster, S. L. Reiner, and M. J. Grusby
IL-21 Inhibits IFN-{gamma} Production in Developing Th1 Cells through the Repression of Eomesodermin Expression
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M. H. Goldschmidt, J. S. Kennedy, D. R. Kennedy, H. Yuan, D. E. Holt, M. L. Casal, A. M. Traas, E. A. Mauldin, P. F. Moore, P. S. Henthorn, et al.
Severe Papillomavirus Infection Progressing to Metastatic Squamous Cell Carcinoma in Bone Marrow-Transplanted X-Linked SCID Dogs.
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M. Pelletier and D. Girard
Differential Effects of IL-15 and IL-21 in Myeloid (CD11b+) and Lymphoid (CD11b-) Bone Marrow Cells
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J. M. Roda, R. Parihar, A. Lehman, A. Mani, S. Tridandapani, and W. E. Carson III
Interleukin-21 Enhances NK Cell Activation in Response to Antibody-Coated Targets
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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
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Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells
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S. J. Burgess, A. I. Marusina, I. Pathmanathan, F. Borrego, and J. E. Coligan
IL-21 Down-Regulates NKG2D/DAP10 Expression on Human NK and CD8+ T Cells
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A. Comes, O. Rosso, A. M. Orengo, E. Di Carlo, C. Sorrentino, R. Meazza, T. Piazza, B. Valzasina, P. Nanni, M. P. Colombo, et al.
CD25+ Regulatory T Cell Depletion Augments Immunotherapy of Micrometastases by an IL-21-Secreting Cellular Vaccine
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J. L. Fornek, L. T. Tygrett, T. J. Waldschmidt, V. Poli, R. C. Rickert, and G. S. Kansas
Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells
Blood, February 1, 2006; 107(3): 1085 - 1091.
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