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.

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.

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).