Christian Neumann 1 , 2 , Frederik Heinrich 1 , Katrin Neumann 1 , 2 , Victoria Junghans 1 , 2 , Mir-Farzin Mashreghi 1 , Jonas Ahlers 1 , 2 , Marko Janke 1 , Christine Rudolph 1 , 2 , Nadine Mockel-Tenbrinck 5 , Anja A. Kühl 3 , Markus M. Heimesaat 4 , Charlotte Esser 6 , Sin-Hyeog Im 7 , Andreas Radbruch 1 , Sascha Rutz , 1 , Alexander Scheffold , 1 , 2
25 August 2014
The transcriptional regulator Blimp-1 is absolutely required for IL-10 production in Th1 cells and limits inflammatory effector T cell responses downstream of IL-12 and IL-27.
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.