IL21R (interleukin 21 receptor)

2012-05-01   Silvano Ferrini , Marina Fabbi 

Lab of Immunotherapy Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy




Atlas Image
Diagram of IL21R gene organization and of the encoded transcripts. The IL21R gene is comprised of 11 exons and encodes for three alternatively spliced transcript variants that use a different first exon. As the first exon is contained within the 5 UTR region the three transcripts encode for the same protein.


The IL21R gene is comprised of 9 exons (+2 alternative first exons), spanning 48.4kb on chromosome 16p11 (Parrish-Novak et al., 2000).
The human IL21R promoter region, contained within nucleotides -789 to +195 (relative to the start of exon 1a) induces the high levels of transcription in reporter assays (Ueda et al., 2002). A critical SP1 binding site is contained in the region from -80 to -20 and is essential for gene expression in human T cells (Wu et al., 2005).
The DNA region (12MB) containing the IL21R gene contains multiple copies of large, duplicated segments (duplicons) originating in other regions of the genome (Loftus et al., 1999), which may predispose to additional duplications or deletions.


Three alternatively spliced transcript variants of 3248, 3361 and 3263 bp, each comprising 9 exons, have been described. They differ only for the alternative usage of a different first exon, which is contained within the 5 UTR region. Therefore these transcript variants encode for the same protein.


Atlas Image
The IL21R requires interaction with the common-gamma chain (γc) for mediating signal transduction upon IL21 binding. The tyrosine kinases JAK1 and JAK3 associate with the receptor complex and mediate receptor chain phosphorylation, recruitment and activation of downstream STAT1 and STAT3 molecules.


The IL21R gene encodes for a 538 aminoacid precursor protein with a 19 aminoacid signal peptide. The mature IL21R protein is a transmembrane glycoprotein with a molecular mass of approximately 75 kDa. IL21R is a type I cytokine receptor with an extracellular domain involved in cytokine binding, which contains one copy of the conserved WSXWS (Trp-Ser-X-Trp-Ser) motif, two fibronectin type-III domains of about 100 amino acids each, and conserved cysteine residues (Parrish-Novak, 2000). IL21R has a transmembrane domain followed by a large intracellular domain that contains the Box 1 and Box 2 elements shown to be important in signal transduction, and six tyrosine residues. The IL-21R also displays a consensus motif for STAT3 binding in its C-terminal tail. IL21R forms a heterodimeric receptor complex with the common gamma-chain (CD132) (Asao et al., 2001), which is also shared as subunit by the receptors for interleukin 2, interleukin 4, interleukin 7, interleukin 9, and interleukin 15.
The crystal structure of IL21 bound to IL21R revealed that the IL21R WSXWS motif is C-mannosylated at the first tryptophan. A sugar chain bridges the two fibronectin domains of the IL21R extracellular portion and anchors at the WSXWS motif through hydrogen bonds (Hamming et al., 2012).


IL21R is expressed on normal B, T and NK lymphoid cells and also on monocyte/macrophages and dendritic cells.
It is of note that also certain lymphoid neoplasias, such as multiple myeloma, Hodgkins and non-Hodgkins lymphomas, B-chronic lymphocytic leukemia and acute T cell leukemia express IL21R.
IL21R expression has been reported on other non-immune cell types such as intestinal epithelium in inflammatory bowel disease (Caruso et al., 2007a), gastric epithelium in Helicobacter pylori infection (Caruso et al., 2007b) and rheumatoid synovium (Jungel et al., 2004).


IL21R protein is localized at the cell membrane.


The IL21R mediates the pleiotropic biological activities of IL21, the lastly identified member of the IL2 family (Parrish-Novak et al., 2000). IL21 co-stimulates mature T and B cell proliferation and differentiation and also potentiate NK cytolytic functions, inducing NK terminal differentiation (Kasaian et al., 2002). IL21 also promotes proliferation, cytotoxic function and IFN-gamma production by murine and human CD8+ effector T cells (Parrish-Novak et al., 2000; Strengell et al., 2003; Di Carlo et al., 2004). IL21R signaling may mediate B cell proliferation and survival or B-cell apoptosis, in relationship to the activation status of the B cells (Ozaki et al., 2004; Metha et al., 2003; Jin et al., 2004). Mice deficient of IL21R (IL21R -/-) show defects in antibody production (in particular decreased IgG1 and increased IgE production in response to antigen stimulation) and reduced CTL responses, although their CD8+ T cell numbers are normal (Ozaki et al., 2002). The IL21/IL21R system is also a regulator of Th17 development and activity (Wei et al., 2007).
The IL21R/common gamma chain complex, upon engagement of its specific ligand IL21, mediates signal transduction through the activation of downstream signaling molecules. These include the tyrosine kinases JAK1 and JAK3, which phosphorylate STAT1 and STAT3 (Zeng et al., 2007; de Totero et al., 2008). Differently from IL2 and IL15, which also use the common gamma chain and JAK3 for signaling and are strong inducers of STAT5 activation, IL21 is a weak inducer of STAT5 activation.
IL21R signaling also leads to weak activation of both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase pathways (PI3K) (Zeng et al., 2007).


IL21R displays structural homologies with other members of the type I cytokine receptor family, such as the IL2Rbeta chain (29% identity, 46% similarity), IL9R, IL4R and IL7R. It has been initially described as an orphan cytokine receptor, structurally related to the IL2Rbeta (Parrish-Novak et al., 2000; Ozaki et al., 2000).



Not yet described. Genetic polymorphisms of IL21R have been described (Heckert et al., 2003). The IL21 variant bearing the (T-83C) genetic polymorphism has been associated with increased IgE levels in females, suggesting a possible role of this IL21R polymorphism in allergy.

Implicated in

Entity name
IL21R is expressed on MM cell lines and primary cells. IL21 induced proliferation and inhibited apoptosis of IL6-dependent human myeloma cell lines. Tumor necrosis factor (TNF) up-regulated the expression of IL21R and combinations of TNF and IL21 synergistically mediated myeloma cell proliferation. Four out of 9 purified primary myeloma cells showed increased DNA synthesis in response to IL21 (Brenne et al., 2002).
Entity name
HTLV-I-infected cell lines and Acute T cell leukemia (ATL)
HTLV-I-infected cell lines and primary ATL cells expressed IL21R mRNA and surface protein. IL21 induced the proliferation of ATL cell lines and activated the phosphorylation of the STAT3 and STAT5. These findings suggest that the IL21/IL21R system may represent a target for the treatment of ATL (Ueda et al., 2005).
Entity name
IL21R as well as IL21 are expressed by HL cells. IL21 activates STAT3 and STAT5 in HL cell lines. Expression of a constitutively active STAT5 molecule in normal human B cells immortalized them. These data suggest that the IL21/IL21R system may activate auto/para-crine loops involved in HL genesis via STAT5 activation (Sheeren et al., 2008).
IL21 also protects HRS cells from CD95 death receptor-induced apoptosis and up-regulates the CC chemokine macrophage-inflammatory protein-3alpha (MIP-3alpha), which attracts regulatory T cells towards HL cells (Lamprecht et al., 2008).
Entity name
SS is a cutaneous CD4+ T-cell lymphoma. IL21 and IL21R are expressed by skin SS cells and STAT3 is constitutively activated. In vitro experiments showed that IL21 itself and the IL2R α-chain are STAT3 target genes in SS cells. These data indicate the existence of an autocrine feedback loop involving IL21/IL21R in the pathogenesis of SS and suggest that IL21 and IL21R are potential therapeutic targets (van der Fits et al., 2012).
ALKL primary tumors and cell lines express IL21R. IL21 induces JAK3/STAT3 signaling and increases growth of ALKL cell lines. Small interfering RNA down-regulation of IL21R decreased both STAT3 activation and cell growth, further supporting a role for IL21/IL21R in ALKL (Dien Bard et al., 2009).
Entity name
B-Chronic Lymphocytic Leukemia (B-CLL)
B-CLL cells express IL21R at variable levels and stimuli such as CpG-ODN (Jahrsdorfer et al., 2006) or CD40L (de Totero et al., 2006) induce up-regulation of IL-21R expression. IL21 mediates apoptosis in B-CLL acting in synergy with these stimuli and may also cooperate with chemotherapy (fludarabine) or anti-CD20 therapeutic antibodies (Gowda et al., 2008).
IL21 may limit the expansion of the CLL clone by inducing apoptosis and counteracting the mitogenic growth factors, such as IL15 (de Totero et al., 2008) and is being considered as a possible therapeutic agent in CLL (Gowda et al., 2008).
Entity name
IL21R is expressed on FL cell lines and primary cells, and IL21 induces apoptosis in some FL cell lines and in primary FL cells at diagnosis (Akamatsu et al., 2007; de Totero et al., 2011). However, other FL cell lines or primary cells from patients in progression express low IL21R and are insensitive to IL21-mediated apoptosis (de Totero et al., 2011).
DLBCL cell lines and primary cells express IL21R and IL21 stimulation leads to cell-cycle arrest and caspase-dependent apoptosis. These effects are STAT3-dependent and involve up-regulation of c-Myc expression. Up-regulated c-Myc decreases the expression of antiapoptotic Bcl-2 and Bcl-X(L) proteins and results in cell death (Sarosiek et al., 2010).
DLBCL is associated in about 28.6-35.5% with BCL6 translocation, which can involve either one of the immunoglobulin genes (IGs) but also other non-IG partners. IL21R gene represents one of such non-Ig fusion partners of BCL6 in the t(3;16) translocation (Ueda et al., 2002).
FISH of lymphoma metaphase cells revealed fusion signals that contained both the BCL6 and IL21R sequences on the der(3)t(3;16) chromosome.
Hybrid gene
As a result of the t(3;16) translocation, the promoter region of IL21R was substituted for the regulatory sequences of BCL6. RT-PCR analyses revealed the presence of a chimeric mRNA consisting of two non-coding exons 1a/1b of IL21R and coding exons of BCL6 in the two lymphoma cells. BCL6 was moderately expressed at the mRNA and protein level under the control of IL21R promoter (Ueda et al., 2002).
Fusion protein
Unknown role.
Entity name
Autoimmune diseases, allergy and neoplasia
Several evidences in experimental murine models indicate that the IL21/IL21R system may be involved in immune-mediated disorders, such as autoimmune diabetes (Spolski et al., 2008), arthritis (Jungel et al., 2004), uveitis (Wang et al., 2011), Sjogrens syndrome (Kang et al., 2011), and systemic lupus erythematosus (SLE) (Herber et al., 2007). The study of the genetic association between single-nucleotide polymorphisms (SNPs) within IL21R and SLE showed a correlation with rs3093301, suggesting that IL21R is a novel susceptibility gene for SLE (Webb et al., 2009). In view of the role of the IL21/IL21R system in autoimmune disorders, anti-IL21 (Maurer et al., 2012) and anti-IL21R (Arai et al., 2010) human antibodies capable of inhibiting IL21 activity are under development for therapy.
In view of its immune-enhancing activities IL21 has been regarded as a suitable molecule for cancer immunotherapy (reviewed in Di Carlo et al., 2007; Sploski and Leonard, 2008; Skak et al., 2008) and clinical phase I clinical trials in melanoma and renal carcinoma have shown acceptable toxicities and clinical activity (Thompson et al., 2008; Schmidt et al., 2010).
In addition, the IL21/IL21R system may play a role in several hematological neoplasias that express the IL21R. The effects of IL21R signaling may however be strikingly different in different neoplastic conditions, as it may transduce mitogenic or survival signals or on the opposite trigger apoptotic cell death. Thus the IL21/IL21R system may represent a therapeutic target for inhibitory molecules in certain hematologic neoplasias, whereas in others IL21 may represent a possible therapeutic agent.
Entity name
Graft verus host disease (GVHD)
Abrogation of IL21 signaling reduces GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses (Hanash et al., 2009). In a murine MHC-mismatched bone marrow transplantation model IL21R-/- donor T cells mediated decreased systemic and gastrointestinal GVHD in transplant recipients. IL21R-/- T cells showed decreased inflammatory cytokine production within the mesenteric lymph nodes, in association with increased regulatory T cell expansion. However, Th-cell cytokine production was maintained peripherally, and IL21R-/- T cells mediated equivalent GVL against hematopoietic tumors. Therefore IL21 is a potential target for therapeutic intervention in bone marrow transplantation (Bucher et al., 2011).
Entity name
Inflammatory bowel disease (IBD)
IL21R is expressed at high levels on intestinal epithelial cells and stomal fibroblasts in IBD. IL21 induced macrophage inflammatory protein-3 alpha (MIP-3alpha), a T-cell chemoattractant in epithelial cells. Therefore IL21 has been involved in the cross-talk between epithelial and immune cells in the gut (Caruso et al., 2007b).
Entity name
Rheumatoid Arthritis (RA)
Both synovial macrophages and synovial fibroblasts expressed IL21R in synovial biopsy samples from RA patients. IL21R is associated with the activated phenotype of fibroblasts (Jungel et al., 2004).
Entity name
Helicobacter pylori (HP) gastritis
Hp infection is associated with gastric inflammation. IL21R is expressed by primary gastric epithelial cells and cell lines, which respond to IL21 by increasing production of MMP-2 and MMP-9. Since IL21 is overexpressed in Hp-infected gastric mucosa it could contribute to increased epithelial gelatinase production (Caruso et al., 2007a).



Two t(3;16)(q27;p11) breakpoints on 16p11 are both localized within the intron 1 of IL-21R gene in two different DLBCL (Ueda et al., 2002).


Pubmed IDLast YearTitleAuthors
176246632007High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma.Akamatsu N et al
205099502010Development and application of a biomarker assay for determining the pharmacodynamic activity of an antagonist candidate biotherapeutic antibody to IL21R in whole blood.Arai M et al
114186232001Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex.Asao H et al
119862332002Interleukin-21 is a growth and survival factor for human myeloma cells.Brenne AT et al
198438832009IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation.Bucher C et al
174429802007IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis.Caruso R et al
147347322004IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice.Di Carlo E et al
196088662009IL-21 contributes to JAK3/STAT3 activation and promotes cell growth in ALK-positive anaplastic large cell lymphoma.Dien Bard J et al
181825772008IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro.Gowda A et al
222351332012Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R.Hamming OJ et al
215968542011Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL.Hanash AM et al
127005982003Novel genetic variation of human interleukin-21 receptor is associated with elevated IgE levels in females.Hecker M et al
173394812007IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression.Herber D et al
168096162006B-chronic lymphocytic leukemia cells and other B cells can produce granzyme B and gain cytotoxic potential after interleukin-21-based activation.Jahrsdörfer B et al
152108292004Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis.Jin H et al
151464162004Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis.Jüngel A et al
220300112011Impact of interleukin-21 in the pathogenesis of primary Sjögren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands.Kang KY et al
119708792002IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity.Kasaian MT et al
186848662008Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha.Lamprecht B et al
104938291999Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q.Loftus BJ et al
223274312012Generation and characterization of human anti-human IL-21 neutralizing monoclonal antibodies.Maurer MF et al
126822412003IL-21 induces the apoptosis of resting and activated primary B cells.Mehta DS et al
110169592000Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain.Ozaki K et al
154944822004Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6.Ozaki K et al
110815042000Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.Parrish-Novak J et al
199656782010Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas.Sarosiek KA et al
182966292008IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis.Scheeren FA et al
209594072010Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial.Schmidt H et al
182591842008Interleukin 21: combination strategies for cancer therapy.Skak K et al
187795742008IL-21 signaling is critical for the development of type I diabetes in the NOD mouse.Spolski R et al
179535102008Interleukin-21: basic biology and implications for cancer and autoimmunity.Spolski R et al
127594222003IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.Strengell M et al
183470082008Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma.Thompson JA et al
118219492002The gene for interleukin-21 receptor is the partner of BCL6 in t(3;16)(q27;p11), which is recurrently observed in diffuse large B-cell lymphoma.Ueda C et al
156388502005Expression of functional interleukin-21 receptor on adult T-cell leukaemia cells.Ueda M et al
215934132011Key role for IL-21 in experimental autoimmune uveitis.Wang L et al
196448542009A polymorphism within IL21R confers risk for systemic lupus erythematosus.Webb R et al
178848122007IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner.Wei L et al
162605922005Interleukin-21 receptor gene induction in human T cells is mediated by T-cell receptor-induced Sp1 activity.Wu Z et al
172347352007The molecular basis of IL-21-mediated proliferation.Zeng R et al
201937342010Heterogeneous expression and function of IL-21R and susceptibility to IL-21-mediated apoptosis in follicular lymphoma Totero D et al
174470632007Role of IL-21 in immune-regulation and tumor immunotherapy.di Carlo E et al
219380132012Autocrine IL-21 stimulation is involved in the maintenance of constitutive STAT3 activation in Sézary syndrome.van der Fits L et al

Other Information

Locus ID:

NCBI: 50615
MIM: 605383
HGNC: 6006
Ensembl: ENSG00000103522


dbSNP: 50615
ClinVar: 50615
TCGA: ENSG00000103522


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Jak-STAT signaling pathwayKEGGko04630
Cytokine-cytokine receptor interactionKEGGhsa04060
Jak-STAT signaling pathwayKEGGhsa04630
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
234400422013Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.58
151464162004Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis.41
212818122011IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain.41
196448542009A polymorphism within IL21R confers risk for systemic lupus erythematosus.39
196448542009A polymorphism within IL21R confers risk for systemic lupus erythematosus.39
215318912011Upregulation of IL-21 receptor on B cells and IL-21 secretion distinguishes novel 2009 H1N1 vaccine responders from nonresponders among HIV-infected persons on combination antiretroviral therapy.39
163910142006Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells.36
157510772005Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis.34
193228992009Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease.33
190753982009IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice.30


Silvano Ferrini ; Marina Fabbi

IL21R (interleukin 21 receptor)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version:

Historical Card

2008-10-01 IL21R (interleukin 21 receptor) by  Silvano Ferrini,Marina Fabbi 

Lab of Immunotherapy Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy