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Intrinsic Reprogramming of Dermal ILC2s in RAG1-Deficient Mice Shapes Cutaneous Inflammation

ABSTRACT: Group 2 innate lymphoid cells (ILC2s) are key regulators of skin immunity and barrier homeostasis. RAG1-deficient (Rag1⁻/⁻) mice are widely used to study ILC2 biology owing to their elevated ILC2 frequencies and absence of adaptive lymphocytes. However, RAG1 is transiently expressed during ILC2 development, raising the question of whether its loss intrinsically alters dermal ILC2 (dILC2) identity and function. We performed transcriptomic and functional analyses of dILC2s from Rag1⁻/⁻ and wild-type mice. RNA sequencing revealed 2,503 differentially expressed genes in Rag1⁻/⁻ dILC2s, including upregulation of Il7r, Thy1, Il5 and Il13, and enrichment of JAK/STAT, PI3K/Akt, IL-23 and apoptosis pathways. Functionally, Rag1⁻/⁻ dILC2s displayed increased basal proliferation and apoptosis. In a DNFB-induced contact hypersensitivity model, Rag1⁻/⁻ mice exhibited attenuated ear swelling and a failure to expand dILC2s upon challenge, in contrast to wild-type mice. Adoptive transfer of lymphocytes partially restored these dynamics, indicating contributions of both intrinsic RAG1-dependent programming and extrinsic adaptive–innate interactions. Our findings demonstrate that RAG1 deficiency fundamentally reprograms dILC2 homeostasis and responsiveness to cutaneous stress. These results highlight the need for careful interpretation of ILC2 biology in Rag1⁻/⁻ models and reveal a previously underappreciated role of RAG1-dependent developmental cues in shaping skin immune responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE317014 | GEO | 2026/07/20

REPOSITORIES: GEO

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