The transcriptional regulator IκBζ is essential for ILC2 effector functions

Abstract Group 2 innate lymphoid cells (ILC2) are the sentinels that ensure tissue homeostasis and engage in the immune response to helminths by secreting type 2 cytokines. Here we show that IκBζ, an atypical member of the IκB family, controls basal IL-5 production by ILC2s and governs their effector program during helminth infection and asthma. Peripheral ILC2s express IκBζ at steady state, and its expression is further induced upon stimulation with IL-33 or IL-25 in an NF-κB- and STAT3/5-dependent manner. Upon activation, IκBζ refines chromatin accessibility at regulatory elements of effector cytokine loci, thereby licensing transcription. Due to reduced type 2 cytokine secretion and impaired proliferative capacity of ILC2s, mice with IκBζ-deficient ILC2s show delayed clearance of the hookworm Nippostrongylus brasiliensis and reduced papain-induced airway inflammation. Taken together, our study highlights the central role of IκBζ in orchestrating the ILC2 effector program in different tissues in health and disease.