Common γ-chain cytokines induce an epigenomically plastic precursor-like KIT⁺ ILC2 state linked to immune disease susceptibility.

Abstract

Group 2 innate lymphoid cells (ILC2s) are key effector cells of type 2 immunity. A subset of ILC2s, which expresses KIT (CD117), display increased phenotypic plasticity and have previously been linked to severe asthma and psoriasis. However, the molecular mechanisms promoting a KIT⁺ ILC2 state remain poorly understood. We defined the molecular basis for the enhanced plasticity of KIT⁺ ILC2s and identified signals that induce this phenotype, including links with immune disease susceptibility. We combined bulk as well as single-cell transcriptome (RNA sequencing) and epigenome (assay for transposase-accessible chromatin using sequencing) analysis with in vitro culture assays using primary human KIT⁺ or KIT^neg ILC2s and multipotent ILC progenitors. Epigenomic data were integrated with genetic risk variants for major human immune diseases. Multiomic analyses revealed that KIT⁺ ILC2s maintain a unique hybrid character marked by expression and open chromatin of genes linked to both ILC progenitors and ILC2 biology. KIT⁺ ILC2s showed extensive epigenomic priming at gene loci related to naive lymphocyte biology, tissue homing, and ILC3 effector functions, including IL17 and IL23R-explaining why KIT⁺ ILC2s are poised to adopt an ILC3-like phenotype. Genetic risk variants for asthma and autoimmunity are enriched in the poised epigenome of KIT⁺ ILC2s. Common γ-chain cytokines IL-2/IL-7 induced and maintained a KIT⁺ phenotype in KIT^neg ILC2s through STAT5 activation. Our study defines KIT⁺ ILC2s as existing in a developmentally immature state and carrying a precursor-like epigenome that promotes phenotypic plasticity and is linked to immune disease susceptibility. Importantly, we identify STAT5-mediated cytokine signals as candidates for therapeutic targeting of KIT⁺ ILC2s.