Christian Neumann 1 , Frederik Heinrich 2 , Katrin Neumann 1 , Victoria Junghans 1 , Mir-Farzin Mashreghi 2 , Jonas Ahlers 1 , Marko Janke 2 , Christine Rudolph 1 , Nadine Mockel-Tenbrinck 3 , Anja A Kühl 4 , Markus M Heimesaat 4 , Charlotte Esser 5 , Sin-Hyeog Im 6 , Andreas Radbruch 2 , Sascha Rutz 7 , Alexander Scheffold 8
Aug 25 2014
Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1-dependent to a Blimp-1-independent pathway in IL-27-induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.