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

Olsthoorn, S. E. M.; Onrust-Van Schoonhoven, A.; de Bruijn, M. J. W.; van Nimwegen, M.; van Beek, G.; de Koning, W.; Trap, L.; van der Ploeg, E. K.; Sanders, M. A.; Surace, L.; Di Santo, J. P.; Hendriks, R. W.; Stadhouders, R.

doi:10.64898/2026.02.27.708582

bioRxiv · 10.64898/2026.02.27.708582

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

Olsthoorn, S. E. M.·Onrust-Van Schoonhoven, A.·de Bruijn, M. J. W.·van Nimwegen, M.·van Beek, G.·de Koning, W.·Trap, L.·van der Ploeg, E. K.·Sanders, M. A.·Surace, L.·Di Santo, J. P.·Hendriks, R. W.·Stadhouders, R.

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Abstract

BackgroundGroup 2 innate lymphoid cells (ILC2s) are key effector cells of type-2 immunity. A subset of ILC2s expresses KIT (CD117), which 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. ObjectiveDefine the molecular basis for the enhanced plasticity of KIT+ ILC2s and identify signals that induce this phenotype, including links with immune disease susceptibility. MethodsWe combine bulk as well as single-cell transcriptome (RNA-seq) and epigenome (ATAC-seq) with in vitro culture assays using primary human KIT+ or KITneg ILC2s and multipotent ILC precursors (ILCPs). Epigenomic data were integrated with genetic risk variants for major human immune diseases. ResultsMulti-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 {gamma}-chain cytokines IL-2 and IL-7 induced a KIT+ phenotype in KITneg ILC2s through STAT5 activation. ConclusionsOur 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.

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Olsthoorn, S. E. M., Onrust-Van Schoonhoven, A., de Bruijn, M. J. W., van Nimwegen, M., van Beek, G., de Koning, W., Trap, L., van der Ploeg, E. K., Sanders, M. A., Surace, L., Di Santo, J. P., Hendriks, R. W., Stadhouders, R.. 2026-03-02. Common γ-chain cytokines induce an epigenomically plastic precursor-like KIT+ ILC2 state linked to immune disease susceptibility. https://doi.org/10.64898/2026.02.27.708582

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