The Yin and Yang of Interleukin-21 in Allergy, Autoimmunity and Cancer

Abstract SCI-6

Interleukin-21 (IL-21) is a four-α-helical bundle type 1 cytokine. Its receptor consists of IL-21R and the common cytokine receptor γ chain, γ_c, which is shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is encoded by the gene that is mutated in humans with X-linked severe combined immunodeficiency (XSCID). Each of these cytokines activates JAK1, which associates with the more distinctive receptor component, and JAK3, which associates with γ_c. IL-21 signals in part via the activation of STAT proteins, with STAT3 being induced more potently than STAT1 or STAT5 proteins. Interestingly, we have demonstrated that STAT3 globally cooperates with IRF4 in the induction of IL-21-regulated genes in T cells. IL-21 is produced by populations of CD4+ T cells, including Th17 cells, T follicular helper cells, and NKT cells. It is a pleiotropic cytokine that exerts a broad and complex array of biological actions on multiple lineages. IL-21 is pro-apoptotic for incompletely activated B cells, thereby serving a role for B cells similar to that of IL-2 related to activation-induced cell death in T cells. However, IL-21 also promotes the expansion and differentiation of activated B cells to plasma cells via its induction of Prdm1, which encodes BLIMP1, and the differentiation of cells into T follicular helper cells via its induction of Bcl6. IL-21 also promotes immunoglobulin class switch, and defective signaling by IL-21 and IL-4 explains the defective B cell function and panhypogammaglobulinemia that is observed in humans with XSCID. In addition, IL-21 has potent actions on CD8+ T cells, cooperating with IL-15 and IL-7 in the expansion of these cells. Conversely, IL-21 has inhibitory effects on antigen presentation by dendritic cells. IL-21 is implicated in multiple forms of autoimmunity, with IL21 and IL21R loci being associated with a range of human autoimmune diseases. Moreover, IL-21 is required for the development of systemic lupus erythematosus, type 1 diabetes mellitus, and experimental autoimmune uveitis in mouse model systems. In contrast to its promotion of autoimmune disease, IL-21 has potential anti-tumor actions, with elimination of established solid tumors in mouse models. In addition to these actions, IL-21 has also been demonstrated to be a potent inducer of IL-10 and thereby to exhibit immunosuppressive effects. In summary, IL-21 has a range of biological actions on multiple lineages, with varied effected related to apoptosis and differentiation, as well as both promoting autoimmunity yet limiting tumor growth. Regulation the actions of IL-21 in vivo therefore has potential clinical utility for a range of diseases.