RAG1 deficiency durably alters dermal group 2 innate lymphoid cells and modifies contact hypersensitivity

Dermal group 2 innate lymphoid cells (dILC2s) contribute to skin homeostasis and inflammatory responses, yet they are frequently studied in Rag1-deficient mice in which the dILC2 compartment may itself be altered.

We compared dILC2s from wild-type (WT) and Rag1-deficient mice by transcriptomic profiling, flow cytometric phenotyping, and functional analysis in a DNFB-induced contact hypersensitivity model with short-term adoptive lymphocyte transfer.

Rag1 deficiency was associated with a marked expansion of dILC2s and broad transcriptional remodeling, including increased expression of Il7r, Thy1, Il5, and Il13, together with enrichment of cytokine signaling, apoptosis, and activation pathways. In vivo, Rag1-deficient mice showed attenuated ear swelling after DNFB challenge and, in contrast to WT mice, failed to expand their absolute dILC2 abundance during inflammation. Short-term adoptive transfer of sensitized WT lymphocytes modestly modified dILC2 dynamics but did not restore the WT inflammatory phenotype. At the cellular level, Rag1-deficient dILC2s displayed a predominantly CD44hi phenotype, increased basal apoptosis, elevated caspase-3/7 activity, and increased BrdU incorporation.

Together, these findings show that Rag1 deficiency durably alters dILC2 state and responsiveness and should be taken into account when interpreting cutaneous inflammation models in immunodeficient mice.