Skin-resident innate lymphoid cells converge on a pathogenic effector state

Abstract

Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally divided into subsets (ILC1/ILC2/ILC3) based on transcription factors (TFs) and cytokines1. In the skin, disease-specific production of ILC3-associated cytokines IL-17 and IL-22 in response to IL-23 signaling contributes to dermal inflammation in psoriasis. However, it is not known if this response is initiated by pre-committed ILCs or by cell state transitions. Here, we show that psoriasis induction in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, without circulatory ILCs, to drive pathology. Single-cell RNA-seq profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum, even at steady state, reflecting fluid ILC states, including a naïve/quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset, expressing both type 2 and 3 cytokines, which we inferred arose via multiple trajectories. We confirmed the transition potential of quiescent and ILC2 states with in vitro experiments, single-cell ATAC-seq, and in vivo fate mapping. Our results highlight the spectrum and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodeling.