Type I IFN promotes ILC2-to-ILC1 plasticity in pre-clinical radiation-induced lung injury

Radiation-induced lung injury (RILI) is a common dose-limiting toxicity after radiotherapy for lung cancer, but the immunological mechanisms contributing to RILI pathogenesis remain poorly understood. Here we analyze a RILI mouse model using high-dose, restricted-field irradiation to the left lung. Flow cytometry and cytokine profiling analysis of innate lymphoid cells (ILC) reveals a radiation-induced shift from lung-resident type 2 ILCs (ILC2) toward pro-inflammatory type 1 ILCs (ILC1). Single-cell RNA-sequencing analysis of mouse lung ILC populations after radiation suggests that type I interferon (IFN) promotes radiation-induced ILC2-to-ILC1 plasticity. In vitro, IFN-β stimulation of mouse ILC2s leads to increased expression of the ILC1 markers T-bet and IFN-γ, while IFN-β stimulation of human peripheral blood mononuclear cells increases the ILC1-to-ILC2 ratio. In vivo, inhibition of type I IFN signaling attenuates lung damage after irradiation in our RILI model. Thus, our findings indicate that radiation-induced type I IFN induces ILC2-to-ILC1 plasticity to contribute to RILI pathogenesis, and suggest that targeting type I IFN signaling may be a therapeutic strategy to mitigate radiation-induced lung injury. Radiotherapy for lung cancer often induces radiation-induced lung injury (RILI). Here, the authors analyze innate lymphoid cells (ILC) in a RILI mouse model, finding that radiation-induced type I interferon directs ILC2-to-ILC1 plasticity, and inhibition of type I interferon signaling reduces ILC plasticity and RILI.