Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 97 (21): 11439-11444

Copyright © 2000 by the National Academy of Sciences.


Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain

Katsutoshi Ozaki*, Kristine Kikly{dagger}, David Michalovich{ddagger}, Peter R. Young§, and Warren J. Leonard*,||

*Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674; and Departments of {dagger}Immunology, {ddagger}Bioinformatics, and §Molecular Biology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406-0939

Accepted for publication August 1, 2000.

Received for publication May 19, 2000.

Abstract: We have identified a type I cytokine receptor, which we have termed novel interleukin receptor (NILR), that is most related to the IL-2 receptor β chain (IL-2Rβ) and physically adjacent to the IL-4 receptor α chain gene on chromosome 16. NILR mRNA is most highly expressed in thymus and spleen, and is induced by phytohemagglutinin in human peripheral blood mononuclear cells. NILR protein was detected on human T cell lymphotropic virus type I-transformed T cell lines, Raji B cells, and YT natural killer-like cells. Artificial homodimerization of the NILR cytoplasmic domain confers proliferation to Ba/F3 murine pro-B cells but not to 32D myeloid progenitor cells or CTLL-2 murine helper T cells. In these latter cells, heterodimerization of IL-2Rβ and the common cytokine receptor {gamma} chain ({gamma}c) cytoplasmic domains allows potent proliferation, whereas such heterodimerization of NILR with {gamma}c does not. This finding suggests that NILR has signaling potential but that a full understanding of its signaling partner(s) is not yet clear. Like IL-2Rβ, NILR associates with Jak1 and mediates Stat5 activation.

Present address: Cardiovascular Diseases, DuPont Pharmaceuticals, Experimental Station, E400/3257, Route 141, Henry Clay Road, Wilmington, DE 19880-0400.

|| To whom reprints requests should be addressed. E-mail: wjl{at}

Communicated by William E. Paul, National Institutes of Health, Bethesda, MD

Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF269133 and AF269134).

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.200360997.

Article and publication date are at

IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts.
L. J. Berglund, D. T. Avery, C. S. Ma, L. Moens, E. K. Deenick, J. Bustamante, S. Boisson-Dupuis, M. Wong, S. Adelstein, P. D. Arkwright, et al. (2013)
Blood 122, 3940-3950
   Abstract »    Full Text »    PDF »
IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation.
J. J. Karrich, L. C. M. Jachimowski, M. Nagasawa, A. Kamp, M. Balzarolo, M. C. Wolkers, C. H. Uittenbogaart, S. Marieke van Ham, and B. Blom (2013)
Blood 121, 3103-3111
   Abstract »    Full Text »    PDF »
Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.
D. Kotlarz, N. Zietara, G. Uzel, T. Weidemann, C. J. Braun, J. Diestelhorst, P. M. Krawitz, P. N. Robinson, J. Hecht, J. Puchalka, et al. (2013)
J. Exp. Med. 210, 433-443
   Abstract »    Full Text »    PDF »
IL-21 Receptor Is Required for the Systemic Accumulation of Activated B and T Lymphocytes in MRL/MpJ-Faslpr/lpr/J Mice.
A. L. Rankin, H. Guay, D. Herber, S. A. Bertino, T. A. Duzanski, Y. Carrier, S. Keegan, M. Senices, N. Stedman, M. Ryan, et al. (2012)
J. Immunol. 188, 1656-1667
   Abstract »    Full Text »    PDF »
Key role for IL-21 in experimental autoimmune uveitis.
L. Wang, C.-R. Yu, H.-P. Kim, W. Liao, W. G. Telford, C. E. Egwuagu, and W. J. Leonard (2011)
PNAS 108, 9542-9547
   Abstract »    Full Text »    PDF »
Stat3 Phosphorylation Mediates Resistance of Primary Human T Cells to Regulatory T Cell Suppression.
W. A. Goodman, A. B. Young, T. S. McCormick, K. D. Cooper, and A. D. Levine (2011)
J. Immunol. 186, 3336-3345
   Abstract »    Full Text »    PDF »
Functional Characterization of a Nonmammalian IL-21: Rainbow Trout Oncorhynchus mykiss IL-21 Upregulates the Expression of the Th Cell Signature Cytokines IFN-{gamma}, IL-10, and IL-22.
T. Wang, P. Diaz-Rosales, M. M. Costa, S. Campbell, M. Snow, B. Collet, S. A. M. Martin, and C. J. Secombes (2011)
J. Immunol. 186, 708-721
   Abstract »    Full Text »    PDF »
A Nonredundant Role for IL-21 Receptor Signaling in Plasma Cell Differentiation and Protective Type 2 Immunity against Gastrointestinal Helminth Infection.
I. L. King, K. Mohrs, and M. Mohrs (2010)
J. Immunol. 185, 6138-6145
   Abstract »    Full Text »    PDF »
Altered Effector CD4+ T Cell Function in IL-21R-/- CD4+ T Cell-Mediated Graft-Versus-Host Disease.
I. Oh, K. Ozaki, A. Meguro, K. Hatanaka, M. Kadowaki, H. Matsu, R. Tatara, K. Sato, Y. Iwakura, S. Nakae, et al. (2010)
J. Immunol. 185, 1920-1926
   Abstract »    Full Text »    PDF »
IL-21 and T follicular helper cells.
R. Spolski and W. J. Leonard (2010)
Int. Immunol. 22, 7-12
   Abstract »    Full Text »    PDF »
Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1.
A. E. Hogg, G. C. Bowick, N. K. Herzog, M. W. Cloyd, and J. J. Endsley (2009)
J. Leukoc. Biol. 86, 1191-1203
   Abstract »    Full Text »    PDF »
IL-21 ensures TGF-{beta}1-induced IgA isotype expression in mouse Peyer's patches.
G.-Y. Seo, J. Youn, and P.-H. Kim (2009)
J. Leukoc. Biol. 85, 744-750
   Abstract »    Full Text »    PDF »
IL-21 Mediates Suppressive Effects via Its Induction of IL-10.
R. Spolski, H.-P. Kim, W. Zhu, D. E. Levy, and W. J. Leonard (2009)
J. Immunol. 182, 2859-2867
   Abstract »    Full Text »    PDF »
Liver Transcriptome Profiles Associated with Strain-Specific Ehrlichia chaffeensis-Induced Hepatitis in SCID Mice.
K. Miura and Y. Rikihisa (2009)
Infect. Immun. 77, 245-254
   Abstract »    Full Text »    PDF »
IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop.
E. Menoret, S. Maiga, G. Descamps, C. Pellat-Deceunynck, C. Fraslon, M. Cappellano, P. Moreau, R. Bataille, and M. Amiot (2008)
J. Immunol. 181, 6837-6842
   Abstract »    Full Text »    PDF »
Hookworm-Induced Persistent Changes to the Immunological Environment of the Lung.
J. J. Reece, M. C. Siracusa, T. L. Southard, C. F. Brayton, J. F. Urban Jr., and A. L. Scott (2008)
Infect. Immun. 76, 3511-3524
   Abstract »    Full Text »    PDF »
Interleukin 21: a cytokine/cytokine receptor system that has come of age.
W. J. Leonard, R. Zeng, and R. Spolski (2008)
J. Leukoc. Biol. 84, 348-356
   Abstract »    Full Text »    PDF »
IL-21 promotes survival and maintains a naive phenotype in human CD4+ T lymphocytes.
S. Ferrari-Lacraz, R. Chicheportiche, G. Schneiter, N. Molnarfi, J. Villard, and J.-M. Dayer (2008)
Int. Immunol. 20, 1009-1018
   Abstract »    Full Text »    PDF »
IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy.
C. S. Hinrichs, R. Spolski, C. M. Paulos, L. Gattinoni, K. W. Kerstann, D. C. Palmer, C. A. Klebanoff, S. A. Rosenberg, W. J. Leonard, and N. P. Restifo (2008)
Blood 111, 5326-5333
   Abstract »    Full Text »    PDF »
IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis.
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. (2008)
Blood 111, 4706-4715
   Abstract »    Full Text »    PDF »
Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus.
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. (2008)
Ann Rheum Dis 67, 458-461
   Abstract »    Full Text »    PDF »
Autocrine Regulation of IL-21 Production in Human T Lymphocytes.
F. Caprioli, M. Sarra, R. Caruso, C. Stolfi, D. Fina, G. Sica, T. T. MacDonald, F. Pallone, and G. Monteleone (2008)
J. Immunol. 180, 1800-1807
   Abstract »    Full Text »    PDF »
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.
D. de Totero, R. Meazza, M. Capaia, M. Fabbi, B. Azzarone, E. Balleari, M. Gobbi, G. Cutrona, M. Ferrarini, and S. Ferrini (2008)
Blood 111, 517-524
   Abstract »    Full Text »    PDF »
Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4+ T cell subsets.
T. Onoda, M. Rahman, H. Nara, A. Araki, K. Makabe, K. Tsumoto, I. Kumagai, T. Kudo, N. Ishii, N. Tanaka, et al. (2007)
Int. Immunol. 19, 1191-1199
   Abstract »    Full Text »    PDF »
IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells.
S. Liu, G. Lizee, Y. Lou, C. Liu, W. W. Overwijk, G. Wang, and P. Hwu (2007)
Int. Immunol. 19, 1213-1221
   Abstract »    Full Text »    PDF »
IL-21 Induces Apoptosis of Antigen-Specific CD8+ T Lymphocytes.
B. R. Barker, J. G. Parvani, D. Meyer, A. S. Hey, K. Skak, and N. L. Letvin (2007)
J. Immunol. 179, 3596-3603
   Abstract »    Full Text »    PDF »
IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade.
V. Ostiguy, E.-L. Allard, M. Marquis, J. Leignadier, and N. Labrecque (2007)
J. Leukoc. Biol. 82, 645-656
   Abstract »    Full Text »    PDF »
The molecular basis of IL-21-mediated proliferation.
R. Zeng, R. Spolski, E. Casas, W. Zhu, D. E. Levy, and W. J. Leonard (2007)
Blood 109, 4135-4142
   Abstract »    Full Text »    PDF »
IL-21 Is Highly Produced in Helicobacter pylori-Infected Gastric Mucosa and Promotes Gelatinases Synthesis.
R. Caruso, D. Fina, I. Peluso, M. C. Fantini, C. Tosti, G. D. V. Blanco, O. A. Paoluzi, F. Caprioli, F. Andrei, C. Stolfi, et al. (2007)
J. Immunol. 178, 5957-5965
   Abstract »    Full Text »    PDF »
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).
L. White, S. Krishnan, N. Strbo, H. Liu, M. A. Kolber, M. G. Lichtenheld, R. N. Pahwa, and S. Pahwa (2007)
Blood 109, 3873-3880
   Abstract »    Full Text »    PDF »
IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo.
A. Frohlich, B. J. Marsland, I. Sonderegger, M. Kurrer, M. R. Hodge, N. L. Harris, and M. Kopf (2007)
Blood 109, 2023-2031
   Abstract »    Full Text »    PDF »
IL-21 Inhibits IFN-{gamma} Production in Developing Th1 Cells through the Repression of Eomesodermin Expression.
A. Suto, A. L. Wurster, S. L. Reiner, and M. J. Grusby (2006)
J. Immunol. 177, 3721-3727
   Abstract »    Full Text »    PDF »
Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells.
D. de Totero, R. Meazza, S. Zupo, G. Cutrona, S. Matis, M. Colombo, E. Balleari, I. Pierri, M. Fabbi, M. Capaia, et al. (2006)
Blood 107, 3708-3715
   Abstract »    Full Text »    PDF »
CD25+ Regulatory T Cell Depletion Augments Immunotherapy of Micrometastases by an IL-21-Secreting Cellular Vaccine.
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. (2006)
J. Immunol. 176, 1750-1758
   Abstract »    Full Text »    PDF »
Effect of IL-21 on NK cells derived from different umbilical cord blood populations.
S. A. Perez, L. G. Mahaira, P. A. Sotiropoulou, A. D. Gritzapis, E. G. Iliopoulou, D. K. Niarchos, N. T. Cacoullos, Y. G. Kavalakis, A. I. Antsaklis, N. N. Sotiriadou, et al. (2006)
Int. Immunol. 18, 49-58
   Abstract »    Full Text »    PDF »
IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells.
R. Ettinger, G. P. Sims, A.-M. Fairhurst, R. Robbins, Y. S. da Silva, R. Spolski, W. J. Leonard, and P. E. Lipsky (2005)
J. Immunol. 175, 7867-7879
   Abstract »    Full Text »    PDF »
Interleukin-21 Receptor Gene Induction in Human T Cells Is Mediated by T-Cell Receptor-Induced Sp1 Activity.
Z. Wu, H.-P. Kim, H.-H. Xue, H. Liu, K. Zhao, and W. J. Leonard (2005)
Mol. Cell. Biol. 25, 9741-9752
   Abstract »    Full Text »    PDF »
IL-21 Sustains CD28 Expression on IL-15-Activated Human Naive CD8+ T Cells.
N. L. Alves, F. A. Arosa, and R. A. W. van Lier (2005)
J. Immunol. 175, 755-762
   Abstract »    Full Text »    PDF »
Calcium-dependent Activation of Interleukin-21 Gene Expression in T Cells.
H.-P. Kim, L. L. Korn, A. M. Gamero, and W. J. Leonard (2005)
J. Biol. Chem. 280, 25291-25297
   Abstract »    Full Text »    PDF »
Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.
R. Zeng, R. Spolski, S. E. Finkelstein, S. Oh, P. E. Kovanen, C. S. Hinrichs, C. A. Pise-Masison, M. F. Radonovich, J. N. Brady, N. P. Restifo, et al. (2005)
J. Exp. Med. 201, 139-148
   Abstract »    Full Text »    PDF »
In Vivo and In Vitro Roles of IL-21 in Inflammation.
M. Pelletier, A. Bouchard, and D. Girard (2004)
J. Immunol. 173, 7521-7530
   Abstract »    Full Text »    PDF »
Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-6.
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. (2004)
J. Immunol. 173, 5361-5371
   Abstract »    Full Text »    PDF »
Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis.
H. Jin, R. Carrio, A. Yu, and T. R. Malek (2004)
J. Immunol. 173, 657-665
   Abstract »    Full Text »    PDF »
Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells.
J. Pene, J.-F. Gauchat, S. Lecart, E. Drouet, P. Guglielmi, V. Boulay, A. Delwail, D. Foster, J.-C. Lecron, and H. Yssel (2004)
J. Immunol. 172, 5154-5157
   Abstract »    Full Text »    PDF »
IL-21 Induces Tumor Rejection by Specific CTL and IFN-{gamma}-Dependent CXC Chemokines in Syngeneic Mice.
E. Di Carlo, A. Comes, A. M. Orengo, O. Rosso, R. Meazza, P. Musiani, M. P. Colombo, and S. Ferrini (2004)
J. Immunol. 172, 1540-1547
   Abstract »    Full Text »    PDF »
In Vivo Antitumor Activity of Interleukin 21 Mediated by Natural Killer Cells.
G. Wang, M. Tschoi, R. Spolski, Y. Lou, K. Ozaki, C. Feng, G. Kim, W. J. Leonard, and P. Hwu (2003)
Cancer Res. 63, 9016-9022
   Abstract »    Full Text »    PDF »
IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-{gamma}.
H.-L. Ma, M. J. Whitters, R. F. Konz, M. Senices, D. A. Young, M. J. Grusby, M. Collins, and K. Dunussi-Joannopoulos (2003)
J. Immunol. 171, 608-615
   Abstract »    Full Text »    PDF »
IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-{gamma} Production in Human NK and T Cells.
M. Strengell, S. Matikainen, J. Siren, A. Lehtonen, D. Foster, I. Julkunen, and T. Sareneva (2003)
J. Immunol. 170, 5464-5469
   Abstract »    Full Text »    PDF »
IL-21 Induces the Apoptosis of Resting and Activated Primary B Cells.
D. S. Mehta, A. L. Wurster, M. J. Whitters, D. A. Young, M. Collins, and M. J. Grusby (2003)
J. Immunol. 170, 4111-4118
   Abstract »    Full Text »    PDF »
Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cepsilon transcription of IL-4-stimulated B cells.
A. Suto, H. Nakajima, K. Hirose, K. Suzuki, S.-i. Kagami, Y. Seto, A. Hoshimoto, Y. Saito, D. C. Foster, and I. Iwamoto (2002)
Blood 100, 4565-4573
   Abstract »    Full Text »    PDF »
A Critical Role for IL-21 in Regulating Immunoglobulin Production.
K. Ozaki, R. Spolski, C. G. Feng, C.-F. Qi, J. Cheng, A. Sher, H. C. Morse III, C. Liu, P. L. Schwartzberg, and W. J. Leonard (2002)
Science 298, 1630-1634
   Abstract »    Full Text »    PDF »
Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses.
J. Parrish-Novak, D. C. Foster, R. D. Holly, and C. H. Clegg (2002)
J. Leukoc. Biol. 72, 856-863
   Abstract »    Full Text »    PDF »
Enforced Expression of Bcl-2 Restores the Number of NK Cells, But Does Not Rescue the Impaired Development of NKT Cells or Intraepithelial Lymphocytes, in IL-2/IL-15 Receptor {beta}-Chain-Deficient Mice.
M. Minagawa, H. Watanabe, C. Miyaji, K. Tomiyama, H. Shimura, A. Ito, M. Ito, J. Domen, I. L. Weissman, and K. Kawai (2002)
J. Immunol. 169, 4153-4160
   Abstract »    Full Text »    PDF »
Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon {gamma}-producing Th1 Cells.
A. L. Wurster, V. L. Rodgers, A. R. Satoskar, M. J. Whitters, D. A. Young, M. Collins, and M. J. Grusby (2002)
J. Exp. Med. 196, 969-977
   Abstract »    Full Text »    PDF »
IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response.
M. Strengell, T. Sareneva, D. Foster, I. Julkunen, and S. Matikainen (2002)
J. Immunol. 169, 3600-3605
   Abstract »    Full Text »    PDF »
Cytokine and Cytokine Receptor Pleiotropy and Redundancy.
K. Ozaki and W. J. Leonard (2002)
J. Biol. Chem. 277, 29355-29358
   Full Text »    PDF »
Interleukin-21 is a growth and survival factor for human myeloma cells.
A.-T. Brenne, T. Baade Ro, A. Waage, A. Sundan, M. Borset, and H. Hjorth-Hansen (2002)
Blood 99, 3756-3762
   Abstract »    Full Text »    PDF »
Interleukin-7: from bench to clinic.
T. J. Fry and C. L. Mackall (2002)
Blood 99, 3892-3904
   Full Text »    PDF »
Cutting Edge: The Common {gamma}-Chain Is an Indispensable Subunit of the IL-21 Receptor Complex.
H. Asao, C. Okuyama, S. Kumaki, N. Ishii, S. Tsuchiya, D. Foster, and K. Sugamura (2001)
J. Immunol. 167, 1-5
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882