Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation

Key Points The receptor for the cytokine interleukin-21 (IL-21) contains the common cytokine-receptor γ-chain, so IL-21 is one of the cytokines that has its effects ablated in individuals with X-linked severe combined immunodeficiency. Although IL-21 is expressed only by CD4 + T cells, its receptor is found at the cell surface of all T cells, B cells, natural killer (NK) cells, dendritic cells (DCs) and keratinocytes, thereby implying that IL-21 has a diverse range of effects. The effects of IL-21 on B cells are context dependent, and they include the induction of apoptosis in naive B cells and, after co-activation with signals from T cells, the induction of differentiation of B cells into plasma cells, through upregulation of expression of B-lymphocyte-induced maturation protein 1 (BLIMP1). IL-21 augments the proliferation of NK cells and leads to the acquisition of a functional cytotoxic state. In vivo treatment with IL-21 leads to increased cytotoxic activity of NK cells and to the induction of a strong antitumour activity in several models of cancer. IL-21 has a synergistic effect on the clonal expansion of CD8 + T cells when delivered in combination with either IL-7 or IL-15. This effect correlates with the ability of IL-21 to promote both increased cytotoxic activity of CD8 + T cells and potent antitumour effects by these cells. IL-21 can negatively control immune responses through its inhibitory effects on DC differentiation and its apoptotic effects on activated NK cells. Our knowledge of the basic biology of IL-21 indicates that there are clinical situations, such as those in autoimmune disease, allergy and cancer, in which either ablation or augmentation of IL-21-mediated signalling might have therapeutic benefit. The interleukin-21 (IL-21)–IL-21-receptor system was discovered in 2000. It was immediately of great interest because of the homology of IL-21 to IL-2, IL-4 and IL-15, and of the IL-21-receptor subunit IL-21R to the β-subunit of the IL-2 receptor, and because the IL-21 receptor also contains the common cytokine-receptor γ-chain, the protein that is mutated in X-linked severe combined immunodeficiency. As we discuss, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells. Moreover, it has antitumour activity and might have a role in the development of autoimmunity,