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

Journal of Neuroinflammation

Laurie E. Harrington¹  Etty Benveniste¹  Susan Nozell¹  Rajani Rajbhandari¹  Ian L. McWilliams¹ 

[1] Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 845 19th Street South, BBRB 471, Birmingham 35294, AL, USA

关键词: GM-CSF;    Th1;    Th17;    MS;    EAE;    STAT4;   

Others  :  1221940
DOI  :  10.1186/s12974-015-0351-3

 received in 2015-04-09, accepted in 2015-06-19,  发布年份 2015

【 摘 要 】

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 _35–55peptide 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.

【 授权许可】

   
2015 McWilliams et al.

【 图 表 】

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