Interleukin-21 Receptor (IL-21 R )is a type I transmembrane glycoprotein within the class I cytokine receptor family (1). IL-21 R associates with the common gamma  chain ( gamma _c) which is also a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (2, 3). Mature human IL-21 R consists of a 213 amino acid (aa) extracellular domain (ECD) with 4 conserved cysteine residues, a fibronectin type III domain, and a WSxWS motif, followed by a 21 aa transmembrane domain and a 285 aa cytoplasmic domain with a Box 1 motif, a kinase domain, and several sites for tyrosine phosphorylation (4, 5). Within the ECD, human IL-21 R shares 69% aa identity with mouse and rat IL-21 R, respectively. IL-21 R is expressed mainly on B cells (highest on mature, activated, follicular and germinal center B cells), NK cells, and activated T cells, but is also found on dendritic cells, alternatively activated macrophages, intestinal lamina propria fibroblasts and epithelial cells, and keratinocytes (1, 4, 5). Both IL-21 and IL-4 are necessary for efficient B cell IgG1 production and normal germinal center architecture (6). B cell IL-21 R engagement induces Blimp-1 (which mediates plasma cell differentiation) and is important for memory responses (7, 8). IL-21 R engagement enhances NK cell mediated cytotoxic activity and IFN-gamma production (4, 9), control of viral infection and tumor growth by CD8 ⁺ T cells (10), development of regulatory T cells (11), IL-23 responsiveness of encephalitogenic Th17 cells (12), but suppresses the accumulation of IL-17 secreting gamma δ T cells in the airway (13). IL-21 R expression is often upregulated in allergic skin inflammation, systemic lupus erythematosus and diffuse large B cell lymphoma (DLBCL) (14, 15).