The impact of skin-like CD103+ ILC2s on lung immunity

Introduction/Rationale: Proper lung function involves tissue-resident immune cells that participate in homeostasis but also protect against further multiple perturbations. Although the “gut-lung” axis has been described, our study addressed a novel paradigm by which skin ILC2s (skILC2) become educated post-birth during interactions with a commensal hair follicle mite, Demodex, proliferate, exit their tissue of developmental origin, and transit to the lung, termed ex_skILC2s. Dissecting how ex_skILC2s impact the lung microenvironment may reveal novel mechanistic ways to safely promote tissue tolerance to allergens and infectious challenges in preemptive ways that open novel therapeutic strategies for improving lung health.

Methods: We used a combination of spectral flow cytometry, scRNA-seq, tissue imaging, parabiosis, infectious (Nippostrongylus (Nb), Influenza), and allergic (OVA, alternaria) models to test our hypothesis.

Results: We show that WT mice infected with Demodex triggered a distinct skin ILC2 subset with a mixed type 2-3 cytokine repertoire, which expands, egresses the skin, enters the blood, and infiltrates into lungs, where they adapt and establish long-term residency. We demonstrate ex_skILC2s in lung are the first group of ILC to be activated upon challenge by the migratory helminth, Nippostrongylus brasiliensis (Nb). In the chronic phase, ex_skILC2s synergize with lung resident ILC2s (nILC2s), newly recruited gut inflammatory ILC2s (iILC2s), and de novo differentiated ILC precursors (ILCPs), to reshape the lung ILC2 landscape. We found that the presence of ex-skILC2s and their distinct activation kinetics play a role in promoting lung tissue repair during the resolution of inflammation after Nb infection.

Conclusion: Our study highlights that the accumulation of ex_skILC2s complements the natural lung immune cell repertoire in ways that enhance the homeostasis and resilience of the organ to diverse post-birth perturbations.