New player in the generation of T_H17 cells

T helper 17 (T_H17) cells comprise a recently identified T_H-cell lineage that has a pro-inflammatory role in autoimmunity and tissue inflammation. Now, three groups report that the cytokine interleukin-21 (IL-21) is not only produced by T_H17 cells but is also a potent and necessary inducer of T_H17-cell differentiation.

The differentiation of T_H17 cells is initiated by transforming growth factor-β (TGFβ) and IL-6, and IL-23 is additionally required for T_H17-cell differentiation in vivo. The transcription factors signal transduction and activator of transcription 3 (STAT3) and retinoic-acid-receptor-related orphan receptor-γ (RORγ) mediate lineage commitment.

Using gene-expression analysis, Nurieva and colleagues compared T_H17 cells with the other known T_H-cell subsets (T_H1 and T_H2 cells) and found that expression of Il21 mRNA was significantly higher in T_H17 cells compared with the other effector cells. They next investigated how IL-21 expression is regulated in T_H17 cells and found that it is upregulated in response to IL-6 but not to TGFβ or IL-23. IL-21 expression was severely impaired in STAT3-deficient cells, but cells lacking RORγ produced similar levels of IL-21 compared with wild-type T cells. So, IL-21 expression by T_H17 cells is dependent on STAT3, whereas IL-17 expression is dependent on both STAT3 and RORγ. Similar results were also obtained by Zhou and colleagues.

In vitro stimulation experiments showed that IL-21-deficient T cells were defective in differentiating into T_H17 cells and this was associated with enhanced differentiation of cells expressing the transcription factor forkhead box P3 (FOXP3), which is associated with the generation of regulatory T cells (T_Reg cells). Further experiments suggested that IL-21 is acting in an autocrine manner, as does interferon-γ (IFNγ) for T_H1 cells and as does IL-4 for T_H2 cells. Finally, when the authors induced experimental autoimmune encephalomyelitis (EAE; a disease in which T_H17 cells are known to be pathogenic) in IL-21-deficient mice, they found that the lack of IL-21 impaired the generation of T_H17 cells and ameliorated the disease.

Previous work from Vijay Kuchroo's group had suggested a reciprocal relationship in the generation of T_H17 cells versus T_Reg cells, in which IL-6 is pivotal in controlling T_H17-cell-lineage specification. In the present study, when Korn and colleagues crossed IL-6-deficient mice with green-fluorescent-protein-labelled FOXP3 knock-in mice and EAE was induced, T_H17 cells did not develop but the mice had higher numbers of CD4⁺CD25⁺FOXP3⁺ T_Reg cells, which was in line with their predictions. As it was possible that the IL-6-deficient environment led to the expansion of T_Reg cells at the expense of effector T cells, the authors deleted T_Reg cells in IL-6-deficient mice and expected to observe induction of autoimmunity mediated by IFNγ-producing T_H1 cells but not T_H17 cells. As expected, these T_Reg-cell-depleted mice were susceptible to EAE. However, they unexpectedly found that IL-17 production was almost similar to wild-type levels, suggesting that T_H17 cells could be generated in vivo in the absence of IL-6. By testing a number of candidate cytokines that could suppress the TGFβ-mediated induction of FOXP3 expression, the authors showed that IL-21 in combination with TGFβ could suppress both FOXP3 expression and induce IL-17 production in naive T cells. However, the frequency of T_H17 cells induced by TGFβ plus IL-21 was lower than that stimulated by TGFβ plus IL-6. Further experiments led the authors to suggest that TGFβ and IL-6 together initiate the differentiation of T_H17 cells, which then produce IL-21 and this creates an amplification loop for further generation of T_H17 cells.

The experiments conducted by Zhou and colleagues yielded similar data — they found that IL-6 induced STAT3-dependent but RORγt-independent expression of IL-21. IL-21 then acts in a self-amplifying loop and cooperates with TGFβ in a RORγt-dependent pathway to induce IL-17 production. IL-21 production also induces expression of the IL-23 receptor, enabling the IL-23 that is produced by antigen-presenting cells to act together with TGFβ to induce the expression of IL-17 and other cytokines.

Together these studies reveal a role for IL-21 in the generation of T_H17 cells and suggest that IL-21, together with IL-6 and IL-23, might be new targets for the therapy of inflammatory diseases.