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

CD4+ T helper 2 (Th2) cells and their innate counterpart, group 2 innate lymphoid cells (ILC2s), drive type 2 immune responses, which protect against helminth infection and induce allergic inflammation. Although both cell types express an overlapping set of effector molecules, the identity of key transcription factors and how they differentially regulate gene expression in each cell type has not been determined. Here, we demonstrate that the transcription factor NF-kB is induced upon stimulation by the alarmin IL-33 in ILC2s and by TCR engagement in Th2 cells, yet NF-kB is essential for the function and expression of type 2 cytokines in ILC2s but not in Th2 cells. In ILC2s, the regulatory regions of key type 2 genes exist in an open chromatin conformation, which can be rapidly occupied by NF-kB following IL-33 stimulation. However, the same regulatory regions are less accessible in unstimulated Th2 cells, and other TCR-induced transcription factors such as NFAT play a more important role in regulating type 2 cytokine expression in Th2 cells. Thus, our results demonstrate a critical role of NF-kB in modulating type 2 immunity in a cell type-specific manner and reveal a remarkable plasticity of innate and adaptive lymphocytes in the use of pre-existing epigenetic states to differentially regulate the same set of effector genes. Integrated analysis of epigenome and transcriptome data from type 2 innate lymphoid cells and their adaptive counterpart, CD4+ T helper 2 cells.