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

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. ABSTRACT 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, so these findings have implications for the treatment of cancer and autoimmune diseases. Access through

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CONTENT BEING VIEWED BY OTHERS THE IL-17 FAMILY IN DISEASES: FROM BENCH TO BEDSIDE Article Open access 11 October 2023 IL-30† (IL-27A): A FAMILIAR STRANGER IN IMMUNITY, INFLAMMATION, AND

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comments. This research was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute, National Institutes of Health (United States). AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, 20892-1674, Maryland, USA Warren J. Leonard & Rosanne Spolski Authors

* Warren J. Leonard View author publications You can also search for this author inPubMed Google Scholar * Rosanne Spolski View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Warren J. Leonard. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS

RELATED LINKS DATABASES ENTREZ GENE γc IL-2 IL-4 IL-7 IL-9 IL-15 IL-21 IL-21R JAK1 JAK3 STAT1 STAT3 STAT5A STAT5B GLOSSARY * TYPE I CYTOKINE A member of a family of cytokines that all have a

four αhelical bundle structure and signal through type-I-cytokine receptors by mechanisms that include the Janus activated kinase (JAK)–signal transducer and activator of transcription

(STAT) pathway. These cytokines include growth hormone, prolactin, thrombopoietin, erythropoietin and many interleukins. * COMMON CYTOKINE-RECEPTOR γ-CHAIN (γc). A chain that is present in

type-I-cytokine receptors. It was first discovered as the γ-chain of the interleukin-2 (IL-2) receptor and was subsequently shown also to be present in the receptors for IL-4, IL-7, IL-9,

IL-15 and IL-21. It is mutated in humans with X-linked severe combined immunodeficiency. * EXPRESSED-SEQUENCE-TAG-BASED SEQUENCING An expressed sequence tag (EST) is a partial cDNA sequence

that can provide information to identify and isolate a complete gene. * T-CELL-DEPENDENT ANTIGEN A protein antigen that needs to be recognized by T helper cells (in the context of MHC

molecules) and requires cooperation between these antigen-specific T cells and B cells for a specific antibody response to be generated. * CLASS SWITCHING A region-specific recombination

process that occurs in antigen-activated B cells. This occurs between switch-region DNA sequences and results in a change in the class of antibody that is produced — from IgM to either IgG,

IgA or IgE. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of these antibody classes to activate the appropriate downstream

effector mechanisms. * X-CHROMOSOME INACTIVATION A process in which one of the two X chromosomes in females undergoes heterochromatization in diploid cells, resulting in its

'inactivation'. This process can have important genetic consequences in individuals who have a defective gene on one of their two X chromosomes. * ACTIVATION-INDUCED CELL DEATH

(AICD). A process in which activated T cells undergo cell death after engagement of death receptors, such as CD95 or the tumour-necrosis-factor receptor, or after exposure to reactive oxygen

species. * ANNEXIN V A molecule that binds phosphatidylserine, which is usually located on the inner leaflet of the plasma membrane but flips to the outer leaflet during apoptosis. Positive

staining with annexin V is an indicator of apoptosis. * POST-SWITCH B CELL A B cell that no longer expresses IgD or IgM but, instead, expresses IgG at the cell surface. * BCL-1 B-CELL LINE

A cell line that was established from a spontaneous mouse B-cell lymphoma (BCL). These cells can be induced to undergo differentiation into plasma cells _in vitro_. * SYSTEMIC LUPUS

ERYTHEMATOSUS (SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood

vessels, especially in the kidney. Patients with SLE generally have abnormal B- and T-cell function. * EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS (EAE). An experimental model for the human

disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with

inflammation and demyelination in the brain and spinal cord. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Leonard, W., Spolski, R. Interleukin-21: a

modulator of lymphoid proliferation, apoptosis and differentiation. _Nat Rev Immunol_ 5, 688–698 (2005). https://doi.org/10.1038/nri1688 Download citation * Issue Date: 01 September 2005 *

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