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

The Journal of allergy and clinical immunology

Authors: Simone E M Olsthoorn, Anne Onrust-Van Schoonhoven, Marjolein J W de Bruijn, Jochem Weekers, Menno van Nimwegen, Gregory van Beek, Willem de Koning, Lianne Trap, Esmee K van der Ploeg, Geert H van Weelden, Mathijs A Sanders, Laura Surace, James P Di Santo, Rudi W Hendriks, Ralph Stadhouders

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 were previously linked to severe asthma and psoriasis. However, the molecular mechanisms promoting a KIT ILC2 state remain poorly understood.

OBJECTIVE: Define the molecular basis for the enhanced plasticity of KIT ILC2s and identify signals that induce this phenotype, including links with immune disease susceptibility.

METHODS: We combined bulk as well as single-cell transcriptome (RNA-seq) and epigenome (ATAC-seq) with in vitro culture assays using primary human KIT or KIT ILC2s and multipotent ILC precursors (ILCPs). Epigenomic data were integrated with genetic risk variants for major human immune diseases.

RESULTS: Multi-omics analyses revealed that KIT ILC2s maintain a unique hybrid character marked by expression and open chromatin of genes linked to both ILCP 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 ILC2s through STAT5 activation.

CONCLUSIONS: Our study defines KIT ILC2s as a developmentally immature state 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.

Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 42309230

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