The Journal of allergy and clinical immunology · 2026
Common γ-chain cytokines induce an epigenomically plastic precursor-like KIT+ ILC2 state linked to immune disease susceptibility.
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Olsthoorn Simone E M, Onrust-Van Schoonhoven Anne, de Bruijn Marjolein J W, Weekers Jochem, van Nimwegen Menno, van Beek Gregory, de Koning Willem, Trap Lianne, van der Ploeg Esmee K, van Weelden Geert H, Sanders Mathijs A, Surace Laura, Di Santo James P, Hendriks Rudi W, Stadhouders Ralph
Аннотация
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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 KITneg ILC2s and multipotent ILC progenitors. Epigenomic data were integrated with genetic risk variants for major human immune diseases.
RESULTS: 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 KITneg ILC2s through STAT5 activation.
CONCLUSIONS: 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.
OBJECTIVE: 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.
METHODS: 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 KITneg ILC2s and multipotent ILC progenitors. Epigenomic data were integrated with genetic risk variants for major human immune diseases.
RESULTS: 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 KITneg ILC2s through STAT5 activation.
CONCLUSIONS: 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.