Molecular regulation of T helper cell self-control

Secretion of the immunosuppressive cytokine interleukin(IL)-10 by pro-inflammatory Th1 and Th17 cells is an essential mechanism to self-limit T cell-mediated inflammation. However, the transcriptional regulation of IL‑10 expression in T cells is insufficiently understood. By directly comparing IL-10-producers with non-producers we found that Th1 and Th17 cells employ different transcriptional networks to regulate IL-10 expression. In Th1 cells, IL-10 expression specifically depends on the transcriptional regulator Blimp-1 downstream of IL-12/IL-27 signaling. Hence T cell-specific Blimp-1 deficiency resulted in enhanced inflammation and immunopathology during T. gondii infection. In contrast in Th17 cells TGF-b antagonized Blimp-1 expression and instead induced a switch to a Blimp-1-independent and c-Maf-dependent IL-10 expression. Despite this differential transcriptional regulation of IL-10 production in distinct Th cell lineages we found that the Notch signaling pathway acts as a potent universal amplifier of IL-10 expression in both Th1 and Th17 cells. Our data illustrate how T helper cells integrate various signals from the environment into a coherent but highly flexible transcriptional regulation of this critical immunosupressive cytokine.