Interleukin-21 receptor (IL-21R) (IL-21R)

The Interleukin-21 receptor (IL-21R) is a type I cytokine receptor that forms a functional heterodimeric complex with the common cytokine receptor gamma chain (CD132) (Parrish-Novak et al., 2000; UniProt Q9HBE5). It is primarily expressed on lymphocytes, including T, B, and NK cells, where it mediates the pleiotropic effects of IL-21 through the activation of the JAK1/JAK3 and STAT3 signaling pathways (Leonard & Wan, 2019). In the context of engineered T cell therapies, such as CAR-T cells, the IL-21/IL-21R axis is a critical target for genetic modulation to overcome the limitations of T cell exhaustion and poor persistence in the tumor microenvironment (Singh et al., 2011). Engineering T cells to constitutively express IL-21R or providing IL-21 signaling promotes a stem cell memory (Tscm) phenotype, which is associated with superior expansion and long-term anti-tumor efficacy in clinical settings (Davis et al., 2007). While enhancing this pathway is a strategy for oncology, its inhibition is being investigated for treating autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis, where overactive IL-21 signaling drives pathology (Spolski & Leonard, 2014). Potential safety concerns associated with modulating this receptor in engineered cells include the risk of cytokine release syndrome (CRS) and unintended systemic inflammation (Santegoets et al., 2019).

Other names

CD360NILRInterleukin-21 receptor subunit alphaIL-21R-alphaInterleukin-21 receptor complex

Agonism of the IL-21R complex activates the JAK/STAT pathway (primarily STAT3) to enhance T cell memory, persistence, and effector function in engineered cell therapies.