Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses.

CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s) drive type 2 immune responses via similar effector molecules that are primarily induced by different signals-interleukin (IL)-33 in ILC2s and TCR engagement in Th2 cells. Here, we examined the transcriptional regulation of type 2 immunity, focusing on the NF-κB pathway, which is differentially activated by TCR engagement or cytokine signaling. Conditional deletion of the NF-κB subunits c-Rel and p65 limited the expression of key type 2 genes, including Il13 and Il5, in ILC2s but not in Th2 cells. Genome-wide analysis revealed that the regulatory regions of such genes exist in an open chromatin state in ILC2s, allowing NF-κB binding upon IL-33 stimulation. These regions are less accessible in unstimulated Th2 cells, where NFAT plays a dominant role. Accordingly, p65 deletion impaired ILC2 activation and function during airway inflammation and helminth infection. Thus, innate and adaptive lymphocytes leverage distinct epigenetic landscapes and transcriptional regulators to control shared effector genes.