Interleukin 21: a cytokine/cytokine receptor system that has come of age

Abstract

Interleukin-21 (IL-21) and its receptor represent the sixth cytokine system whose actions were recognized to require the common cytokine receptor gamma chain. IL-21 is produced by activated CD4+ T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lymphohematopoietic lineages. Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8+ T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells. Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent. The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease.

Fig. 1.

Cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) whose receptors share the common cytokine receptor γ subunit, γ_c. Each of these cytokine receptors also contains one or two more distinctive receptor subunits.

Fig. 2.

The mouse IL-21 receptor (IL-21R) contains six tyrosine residues in its cytoplasmic domain. Y510 is within a consensus Stat3-bibding motif, YXXQ (boxed). TM, transmembrane domain.

Fig. 3.

A model for IL-21R signaling. IL-21 can activate at least three signaling pathways: Jak-STAT, MAPK, and PI 3-kinase pathways.

Fig. 4.

Schematic of the sequential roles of IL-6, IL-21, and IL-23 in Th17 lineage differentiation. IL-6 helps to initiate Th17 differentiation, and via Stat3 induces expression of IL-21 and IL-21R. IL-21 can then induce IL-23R expression, and IL-23 can then act. This overall cytokine cascade then can result in stable Th17 differentiation.

Fig. 5.

Schematic showing the production of IL-21 by activated CD4⁺ T cells including follicular helper T (TFM) cell and natural killer T (NKT) cells and its action on a large array of target cells. Collectively, IL-21 can exert antitumor activity and additionally has effects in inflammation, autoimmunity, and allergic diseases. DC, Dentritic cells; MΦ, macrophages; EC, epithelial cells; Kera., Keratinocytes.