Circulatory ILC2 convert and persist as part of the long-term tissue-resident pool after infection [Infection Timecourse with Vascular Labelling]

Circulating ILC2 can serve as a first line of defense against infection prior to the local expansion of lung-resident ILC2. The fate of these circulating ILC2 and their contribution to the long-term lung-resident ILC2 pool is not understood. Using reporter mice in combination with single cell RNA sequencing (scRNA-seq) and novel applications of Cellular Indexing of Transcriptomes and Epitopes sequencing (CITE-seq), we assessed vascular and parenchymal ILC2 populations during helminth infection and the fate of circulatory ILC2. These studies revealed that circulating ILC2 rapidly convert to a tissue-resident phenotype upon arrival in the lung. Once converted, former circulating ILC2 become largely indistinguishable from lung-resident ILC2 over time. Key gene expression retained by converted ILC2 at the peak of the tissue-resident ILC2 response was related to maintained IL-25-responsiveness and unique cytokine potential. These converted ILC2 accumulate, expand, and persist alongside conventional lung-resident populations even after repeated pulmonary infections. These findings reveal an important contribution of circulating ILC2 to the long-term health and maintenance of the lung-resident ILC2 population.