IL-27 paves different roads to Tr1.

Tr1 cells are non-Foxp3-expressing regulatory CD4(+) T cells that execute suppressor functions by secreting the anti-inflammatory cytokine IL-10. Differentiation of this T-cell subset is facilitated by the heterodimeric cytokine IL-27, which can activate transcription factors such as c-Maf and Ahr to positively regulate the differentiation of Tr1 cells and their IL-10 production. In this issue of the European Journal of Immunology, an alternate transcriptional network regulated by IL-27 to induce IL-10 production in Tr1 cells is reported by Iwasaki et al. [Eur. J. Immunol. 2013. 43: 1063-1073]. This study shows that IL-27 initiates tandem activation of the transcription factors STAT3 and Egr-2 to induce il10 in Tr1 cells in a Blimp1-dependent fashion. These findings indicate a c-Maf/Ahr independent mechanism that activates IL-10 production by Tr1 cells and suggest that Il10 induction may depend on both the cytokine environment and the molecular context. Thus, Tr1 cells may be another example of the remarkable plasticity of CD4(+) T cells and indeed may not constitute a separate lineage of CD4(+) T cells but rather represent a developmental endpoint of several T helper cell differentiation pathways.