NRF2 is a spatiotemporal metabolic hub driving the polyfunctionality of Th2 cells in allergic asthma

Polyfunctional T cell responses are detrimental in immune disorders; however, it is unclear how effector T cell subsets acquire polyfunctionality in tissues. Here, we demonstrate that the activation of Nrf2 is necessary for the differentiation polyfunctional Th2 cells in vivo. Reactive oxygen species (ROS) levels are significantly elevated in lung-infiltrating immune cells during allergic asthma, and inhibiting either ROS or Nrf2 significantly decreases eosinophilia and polyfunctional Th2 cells in the lung. In vivo studies using multiple cell-type specific Nrf2-deficient mice and mixed bone marrow chimeras revealed that cell-intrinsic Nrf2 drives IL-5 and IL-13 expression in Th2 cells independently of IL-33. Mechanistically, Nrf2 promotes optimal OXPHOS and glycolysis capacity by inducing PPARg expression and glucose uptake to drive polyfunctionality of Th2 cells. Blocking Nrf2 reduces IL-5 and IL-13 production from house dust mite allergen-specific Th2 cells obtained from asthma patients. These findings demonstrate that Nrf2 acts as a spatiotemporal metabolic hub driving the differentiation of polyfunctional Th2 cells, which may have therapeutic implications for controlling allergic lung inflammation. To investigate the mechanisms by which effector Th2 cells acquire polyfunctionality, we utilized animal models of allergic asthma. Our hypothesis was that if a cell-intrinsic factor plays a critical role in the polyfunctional program of T cells, its levels would be significantly altered in the lung-infiltrating immune cells compared to those in the draining lymph nodes. We performed RNA-seq and ATAC-seq to obtain epigenetics data of WT and cKO.