JOURNAL OF EXPERIMENTAL MEDICINE, v.211, no.9, pp.1807 - 1819
ROCKEFELLER UNIV PRESS
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) . While effectively blocking IL-10 production from Th1 cells, TGF- 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.