IL-21: A novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses

IL-21 is a recently described type I cytokine produced by activated CD4⁺ T cells that profoundly affects the growth, survival, and functional activation of B, T, and natural killer lymphocytes in concert with other cytokines or activating stimuli. Structurally, IL-21 is predicted to display a 4-helix-bundle-type fold with significant homology to IL-2, IL-4, and IL-15 and mediates its biologic effects through a novel type I cytokine receptor, IL-21R, in conjunction with the common cytokine receptor γ chain (γc) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. As a new member of the γc-dependent cytokine family, there is significant interest in IL-21, in part because of its potential to provide new insights into the immunologic phenotype caused by γc deficiency. IL-21R knockout mice have been generated that have normal lymphoid cell development yet exhibit impaired production of the immunoglobulin IgG₁ and increased IgE responses after immunization. As expected for cytokines that use γc, recent studies indicate that IL-21 induces Janus kinase 1 (JAK1) and JAK3 activation to initiate signal transduction, but unlike these other γc-dependent cytokines, which predominantly activate signal transducer and activator of transcription 5 (STAT5), IL-21 preferentially activates STAT1 and STAT3. IL-21 potently enhances primary antigen responses and the effector functions of T and natural killer cells and stimulates IFN-γ production alone or in concert with other cytokines. Thus, on the basis of primary structure, receptor composition, and biologic activities, IL-21 is a new IL-2-family cytokine that participates in both innate and adaptive immunity and might be important for the development of a T_H1 immune response.