Abstract
Cytokine responsiveness is a critical component of the ability of cells to respond to the extracellular milieu. Transcription factor-mediated regulation of cytokine receptor expression is a common mode of altering responses to the external environment. We identify the transcription factor Twist1 as a component of a STAT3-induced feedback loop that controls IL-6 signals by directly repressing Il6ra. Human and mouse T cells lacking Twist1 have an increased ability to differentiate into Th17 cells. Mice with a T cell-specific deletion of Twist1 demonstrate increased Th17 and T follicular helper cell development, early onset experimental autoimmune encephalomyelitis, and increased antigen-specific antibody responses. Thus, Twist1 has a critical role in limiting both cell-mediated and humoral immunity.
Highlights
Twist1 is a transcriptional repressor that inhibits the development of Th1 cells
We show that Twist1 expression is induced following stimulation with STAT3-inducing cytokines and that it reduces IL-17 production in Th17 cells in vitro and in vivo
Because STAT3 directly binds to the Twist1 promoter in breast cancer cells [38], we speculated that STAT3 might induce Twist1 expression in Th17 cultures
Summary
Twist is a transcriptional repressor that inhibits the development of Th1 cells. Results: Twist impairs Th17 and Tfh cell development by decreasing IL-6-induced STAT3. The signal transducer and activator of transcription factor STAT5 promotes Il4ra and Il12rb expression, genes that are critical, respectively, for IL-4 and IL-12 signaling to stimulate Th2 and Th1 differentiation [12, 13]. The transcription factor GATA3 diminishes expression of Il12rb and Stat that mediate IL-12 responses and prevents Th2 cells from responding to a Th1promoting environment [15, 16]. Whether additional transcription factors regulate the responsiveness of differentiating T cells to STAT3-activating cytokines has not been completely explored. Twist negatively regulates Th1 gene expression and cytokine production through several mechanisms, including decreasing the expression of Il12rb, resulting in diminished STAT4 activation [33]. Twist is a STAT3-induced negative regulator of Th17 and Tfh differentiation, limiting the development of cell-mediated and humoral immunity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
