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

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 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. 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 mog35-55-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. © 2015 mcwilliams et al.