The differentiation of pathogenic Th17 cells is negatively regulated by the transcription factor ELF4 (152.6)

Abstract

Abstract T helper 17 (Th17) cells are potent inducers of tissue inflammation involved in several autoimmune diseases such as multiple sclerosis (MS). Although the importance of environmental factors such as IL-6, IL-21, and IL-23 has been well established, the transcriptional network regulating lineage specification and acquisition of effector function in Th17 cells is not entirely understood. We found that loss of the transcription factor ELF4 led to increased in vitro Th17 differentiation without significant alteration in Th1, Th2, and Treg polarization. The increased differentiation of Elf4-null Th17 cells was also observed in the absence of TGFβ signaling, known to abrogate pathogenicity of Th17 cells, suggesting that polarized Elf4-null CD4+ T cells may be more pathogenic. By using experimental allergic encephalomyelitis (EAE), a mouse model for human MS, we found that Elf4-null mice exhibited an earlier onset and increased severity of disease compared to wild-type mice, supporting a negative role of ELF4 in pathogenicity of Th17 cells in vivo. To understand how ELF4 modulates Th17 differentiation, we investigated cytokine signaling in Elf4-null CD4+ T cells. Increased phosphorylation of STAT3 was observed in Elf4-null CD4+ T cells after 5-min and 30-min IL-6 stimulation. Collectively, our study identified a novel intrinsic regulator that may inhibit Th17 differentiation by dampening cytokine signaling through STAT3 inhibition.