STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE

J Neuroinflammation. 2015 Jun 30:12:128. doi: 10.1186/s12974-015-0351-3.

Abstract

Background: In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, mice genetically deficient in the transcription factor signal transducer and activator of transcription 4 (STAT4) are resistant to disease. In contrast, deletion or inhibition of the Th1-associated cytokines IL-12 or IFNγ which act upstream and downstream of STAT4, respectively, does not ameliorate disease. These discordant findings imply that STAT4 may act in a non-canonical role during EAE. Recently, STAT4 has been shown to regulate GM-CSF production by CD4 T cells and this cytokine is necessary for the induction of EAE. However, it is not known if STAT4 controls GM-CSF production by both Th1 and Th17 effector CD4 T cells.

Methods: This study utilized the MOG(35-55) peptide immunization model of EAE. Intracellular cytokine staining and novel mixed bone marrow chimeric mice were used to study the CD4 T cell-intrinsic role of STAT4 during disease. STAT4 chromatin-immunoprecipitation (ChIP-PCR) experiments were performed to show STAT4 directly interacts with the Csf2 gene loci.

Results: Herein, we demonstrate that STAT4 controls CD4 T cell-intrinsic GM-CSF production by both Th1 and Th17 CD4 T cells during EAE as well as in vitro. Importantly, we show that STAT4 interacts with the Csf2 locus in MOG(35-55)-activated effector CD4 T cells demonstrating direct modulation of GM-CSF.

Conclusions: Overall, these studies illustrate a previously unrecognized role of STAT4 to regulate GM-CSF production by not only Th1 cells, but also Th17 effector CD4 T cell subsets during EAE pathogenesis. Critically, these data highlight for the first time that STAT4 is able to modulate the effector profile of Th17 CD4 T cell subsets, which redefines our current understanding of STAT4 as a Th1-centric factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • STAT4 Transcription Factor / deficiency
  • STAT4 Transcription Factor / genetics
  • STAT4 Transcription Factor / metabolism*
  • Th1 Cells / metabolism*
  • Th1 Cells / pathology
  • Th17 Cells / metabolism*
  • Th17 Cells / pathology

Substances

  • Homeodomain Proteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • RAG-1 protein
  • Granulocyte-Macrophage Colony-Stimulating Factor