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

Ian L Mcwilliams,Susan Nozell,Laurie E Harrington,Etty Benveniste,Rajani Rajbhandari

doi:10.1186/s12974-015-0351-3

Abstract

BackgroundIn 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.MethodsThis study utilized the MOG35–55 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.ResultsHerein, 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 MOG35–55-activated effector CD4 T cells demonstrating direct modulation of GM-CSF.ConclusionsOverall, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0351-3) contains supplementary material, which is available to authorized users.

Highlights

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
STAT4 directly interacts with the Csf2 locus to activate transcription Both in vitro and in vivo, we find that STAT4 signaling is critical for optimal lineage-non-specific GM-CSF expression; these data do not reveal if STAT4 is acting directly to modify the Csf2 locus and/or activate gene transcription
WT and STAT4−/− mice were immunized for EAE, and on day 10, CD4 T cells from the spleen and draining lymph nodes (dLN) were pooled and activated with the MOG35−55 peptide for 5 h

Summary

Introduction

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. Studies using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), have demonstrated that the Th1 and Th17 CD4 T cell subsets are associated with disease onset and that both subsets are capable of causing disease. While both Th1 and Th17 cells can initiate disease, the mechanisms by which these cells mediate inflammation and characteristics of the disease are different [3,4,5].

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