Nr4a1 marks a distinctive ILC2 activation subset in the mouse inflammatory lung

BackgroundGroup 2 innate lymphoid cells (ILC2s) are critical sources of type 2 cytokines and represent one of the major tissue-resident lymphoid cells in the mouse lung. However, the molecular mechanisms underlying ILC2 activation under challenges are not fully understood.ResultsHere, using single-cell transcriptomics, genetic reporters, and gene knockouts, we identify four ILC2 subsets, including two non-activation subsets and two activation subsets, in the mouse acute inflammatory lung. Of note, a distinct activation subset, marked by the transcription factor Nr4a1, paradoxically expresses both tissue-resident memory T cell (Trm), and effector/central memory T cell (Tem/Tcm) signature genes, as well as higher scores of proliferation, activation, and wound healing, all driven by its particular regulons. Furthermore, we demonstrate that the Nr4a1+ILC2s are restrained from activating by the programmed cell death protein-1 (PD-1), which negatively modulates their activation-related regulons. PD-1 deficiency places the non-activation ILC2s in a state that is prone to activation, resulting in Nr4a1+ILC2 differentiation through different activation trajectories. Loss of PD-1 also leads to the expansion of Nr4a1+ILC2s by the increase of their proliferation ability.ConclusionsThe findings show that activated ILC2s are a heterogenous population encompassing distinct subsets that have different propensities, and therefore provide an opportunity to explore PD-1's role in modulating the activity of ILC2s for disease prevention and therapy.

Automated summary

In this study, researchers identified four subsets of innate lymphoid cells (ILC2s) in the mouse acute inflammatory lung and found a distinct activation subset, marked by the transcription factor Nr4a1, which paradoxically expresses both tissue-resident memory T cell and effector/central memory T cell signature genes. They also discovered that programmed cell death protein-1 (PD-1) negatively modulates the activation of Nr4a1+ILC2s. The findings suggest that activated ILC2s are a heterogenous population and provide insights into the role of PD-1 in modulating the activity of ILC2s.