ATF4 is induced by ROS and regulates Th1 and Th17 cells (P6219)

Abstract

Abstract Reactive oxygen species (ROS) play a major role in the pathogenesis of chronic inflammatory and autoimmune diseases. It is well established that ROS modulate T cell-mediated immune responses. However, little is known about underlying molecular mechanisms of how ROS regulate T cell immune responses and how T cells adapt to high levels of ROS. We demonstrated that ROS induced ATF4 in activated T cells. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates cellular redox state and amino acid metabolism. We found that, in the high ROS condition, ATF4-/- Th1 cells failed to produce IFN-γ whereas WT Th1 cells still made large amounts of IFN-γ. Inhibition of ROS by addition of antioxidants recovered the IFN-γ production by ATF4-/- Th1 cells, suggesting ATF4 is critically required for the function of Th1 cells in the presence of high levels of ROS. ATF4-/- antigen presenting cells (APC) promoted IL-17 production, suggesting ATF4 plays an important role in APCs in suppressing Th17-driving cytokines. In addition, we demonstrated that experimental allergic encephalomyelitis (EAE) was exacerbated in ATF4 deficient mice compared with wild type (WT) mice. The number of autoreactive Th1 cells was decreased whereas that of autoreactive Th17 cells was elevated in ATF4-/- mice compared with WT mice. Our study establishes that ATF4 promotes Th1 and suppresses Th17 immune responses and likely plays an important role in autoimmunity and cancer immunology.