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Review
. 2008 Jun;20(3):295-301.
doi: 10.1016/j.coi.2008.02.004. Epub 2008 Jun 12.

The Yin and Yang of interleukin-21 in allergy, autoimmunity and cancer

Rosanne Spolski  1 , Warren J Leonard
Affiliations
Review

The Yin and Yang of interleukin-21 in allergy, autoimmunity and cancer

Rosanne Spolski et al. Curr Opin Immunol. 2008 Jun.

Abstract

IL-21 is a type I cytokine that like IL-2, IL-4, IL-7, IL-9, and IL-15 shares the common cytokine receptor gamma chain, gamma(c). IL-21 is produced by activated CD4(+) T cells, NKT cells, and Th17 cells and has pleiotropic actions on a range of lymphoid lineages. IL-21 regulates immunoglobulin production and drives B cell terminal differentiation into plasma cells, cooperatively expands CD8(+) T cells and drives Th17 differentiation, has inhibitory effects on antigen presentation by dendritic cells, and can be pro-apoptotic for B and NK cells. Moreover, IL-21 has potent anti-tumor effects and is implicated in the development of autoimmune diseases. Regulating IL-21 actions in vivo therefore has clinical potential for a range of diseases and is an area of active investigation.

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Figures

Figure 1
Figure 1. Effects of IL-21 on B cell survival and function
The outcome of IL-21 signaling to the naive B cell is context dependent. (A) In the absence of a signal to the B cell antigen receptor but in the presence of a pathogen-derived signal to toll-like receptors (TLR), IL-21 induces apoptosis of naive B cells. (B) In the presence of a B cell antigen receptor signal as well as a T cell-derived signal such as IL-4, IL-21 enhances naive B cell proliferation, leading to the cooperative regulation of immunoglobulin production mediated by the IL-21 induction of the master switch transcription factor Blimp-1 that leads to plasma cell differentiation. Although IL-21 signals to IgG-expressing B cells are positive, IL-21 induces selective apoptosis of IgE-committed B cells, leading to reduced production of IgE in the presence of IL-21.
Figure 2
Figure 2. Pleiotropic effects of IL-21 on CD4+ T cell subsets
When IL-21 is present during priming of naive CD4+ T cells under conditions leading to Th1 commitment (IL-12 plus anti-IL-4), levels of the transcription factor Eomes are down-regulated, leading to reduced production of IFN-γ. In contrast, the presence of IL-21 during priming under conditions leading to Th2 differentiation (IL-4 plus anti-IFN-γ) has no apparent effect on the production of Th2 cytokines such as IL-4. Priming of naive CD4+ T cells with TGF-β plus IL-6 leads to expression of RORγt, which initiates Th17 lineage commitment. This leads to the production of high levels of IL-21 which has the further effect of inducing the IL-23R on T cells, thus allowing Th17 cells to respond to IL-23 with further expansion and production of IL-17, IL-21, and IL-22, all of which are involved in the propagation of inflammatory responses.
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References

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