The cytokine interleukin-10 (IL-10), which is produced by various immune cells, has a crucial role in limiting inflammation. Recently, its production by distinct subsets of T cells, including T helper 1 (TH1) cells, has been described but the factors that induce its production by T cells are not fully understood. Another unresolved issue is the contradictory role of transforming growth factor-β (TGFβ) in the induction of both regulatory T cells and 'pro-inflammatory' TH17 cells. Now, four papers published in Nature Immunology address these issues, and identify a new pathway by which the immune system can restrain an inflammatory response.

Dendritic cells (DCs) can drive the differentiation of T cells, but they can also respond to factors produced by activated T cells and further regulate an ongoing immune response. Awasthi et al. investigated this process in an effort to understand the factors required for the induction of IL-10-producing T cells. They found that FOXP3+ (forkhead box P3) regulatory T cells, induced by TGFβ, could modify DCs, which in turn could induce IL-10-producing T cells through the production of IL-27 and further amplify this response through the production of TGFβ. These IL-10-producing T cells also produced interferon-γ (IFNγ) and expressed the transcription factor T-bet.

Stumhofer et al. also showed that IL-27 induced the production of IL-10 by CD4+ and CD8+ T cells, and that TGFβ enhanced this effect. IL-27 promoted the differentiation of T cells into IL-10-producing T cells under TH1- and TH2- but not TH17-polarizing conditions, and the generation of these cells was dependent on the transcription factors STAT1 (signal transducer and activator of transcription 1) and STAT3. Interestingly, they found that, in the absence of IL-27, TGFβ plus IL-6 (TH17-polarizing conditions) induced a large population of T cells that produced IL-10 (with or without IL-17) in a STAT3-dependent manner, indicating that IL-6, as well as IL-27, can synergize with TGFβ to induce IL-10 production by T cells.

Under different experimental conditions, Fitzgerald et al. also identified a key role for IL-27 in the differentiation of T cells into IL-10+IFNγ+T-bet+ T cells. Both the Stumhofer and Fitzgerald studies showed that IL-27 suppressed IL-17 production by TH17 cells, and this suppression was partially, but not completely, dependent on the induction of IL-10. In addition, Fitzgerald et al. showed that the exogenous administration of IL-27 reduced the severity of experimental autoimmune encephalomyelitis (EAE) induced by the adoptive transfer of TH1 cells in an IL-10-dependent manner.

It is clear that TGFβ has an important role in the induction of TH17 cells in mice but there is still some confusion as to its role at later stages of the response — McGeachy et al. sought to clarify this issue. They showed that although TGFβ plus IL-6 induced continuous IL-17 production from myelin-reactive T cells, these cytokines induced TH17 cells that were non-pathogenic in an adoptive-transfer model of EAE. Only the transfer of T cells that had been stimulated in vitro with IL-23 induced disease. In addition, TGFβ plus IL-6 but not IL-23 induced the production of IL-10 during the de novo generation of TH17 cells. This IL-10 was maintained by further stimulation with TGFβ plus IL-6 but was lost when the TH17 cells were restimulated with IL-23. This study suggests that TGFβ plus IL-6 drive the differentiation of non-pathogenic TH17 cells that produce IL-10, which mediates a bystander regulatory response, thereby providing a means to regulate pathogenic TH17-cell responses.

Together, these papers show a new mechanism by which the immune system can regulate an inflammatory immune response through the production of IL-27 — probably by DCs that have been modified by regulatory T cells — and the subsequent induction of IL-10-producing T cells. In addition, TGFβ can augment this response, and in the presence of IL-6 can directly promote the differentiation of non-pathogenic TH17 cells that produce IL-10.