title: STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE.
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.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 845 19th Street South, BBRB 471, Birmingham, AL, 35294, USA. IanLMcW@uab.edu.
authors.forename: Ian L
authors.initials: IL
authors.lastname: McWilliams
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 845 19th Street South, BBRB 471, Birmingham, AL, 35294, USA. pokhara@uab.edu.
authors.forename: Rajani
authors.initials: R
authors.lastname: Rajbhandari
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 845 19th Street South, BBRB 471, Birmingham, AL, 35294, USA. Snozell@uab.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Nozell
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 845 19th Street South, BBRB 471, Birmingham, AL, 35294, USA. Tika@uab.edu.
authors.forename: Etty
authors.initials: E
authors.lastname: Benveniste
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 845 19th Street South, BBRB 471, Birmingham, AL, 35294, USA. lharring@uab.edu.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Harrington
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); C064658:RAG-1 protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor