IL-21R is a type I transmembrane protein, belonging to the class I cytokine receptor family. IL-21R contains the WSXWS motif, closely resembling IL-2Rβ and IL-4Rα. Intracellular domain of IL-21R includes the Box 1 and Box 2 elements, which are similar to the IL-9R intracellular region. IL-21R is expressed on B cells and at various levels on NK and T cells, but it is up-regulated after activation. Some studies indicated high levels of IL-21R in some leukemia and lymphoma. IL-21R expression is also elevated by CD40 triggering. IL-21R forms a heterodimer with common γ subunit (CD132), which is shared by the receptors for other interleukins, including IL-2, IL-4, IL-7, IL-9 and IL-15. Upon IL-21 ligation, IL-21R associates with JAK1 and induces phosphorylation cascade and STAT1, 3, 5 transduction pathways. Several evidences shown that IL-21/IL-21R signaling is essential for proliferation and differentiation of B, NK and T cells. In normal B cells, IL-21 mediates cell proliferation, growth arrest, and terminal differentiation, or apoptosis, depending on their activation status. In addition, mice lacking IL-21R have increased production of serum IgE but decreased IgG1. After immunization, antigen-specific IgG production was impaired, indicating IL-21/IL-21R is critical for regulating immunoglobulin production. Though B cell development and acute CD8+ T cell response are normal in IL-21R-deficient mice, development of memory B cells and maintenance of T cell function during chronic viral infection are impaired. IL-21/IL-21R complex can enhance NK cytotoxic activity and IFNγ production. In human, the loss of function in IL-21R gene leads to autosomal recessive IL21R immunodeficiency (IL21RID), resulting in dysfunction of B cells, T cells and NK cells, and a primary immunodeficiency syndrome.?