Role of Blimp-1 in programing Th effector cells into IL-10 producers

J Exp Med. 2014 Aug 25;211(9):1807-19. doi: 10.1084/jem.20131548. Epub 2014 Jul 29.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / genetics
  • Interleukin-12 / metabolism
  • Interleukins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-maf / antagonists & inhibitors
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / immunology
  • Receptors, Notch / metabolism
  • STAT4 Transcription Factor / deficiency
  • STAT4 Transcription Factor / genetics
  • STAT4 Transcription Factor / metabolism
  • Signal Transduction
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism*
  • Toxoplasmosis / genetics
  • Toxoplasmosis / immunology
  • Toxoplasmosis / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Transforming Growth Factor beta / metabolism

Substances

  • IL10 protein, mouse
  • Il27 protein, mouse
  • Interleukins
  • Maf protein, mouse
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins c-maf
  • Receptors, Notch
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-12
  • Positive Regulatory Domain I-Binding Factor 1