Determining the fate of pulmonary iILC2s in helminth infection

Abstract

Abstract Group 2 Innate Lymphoid Cells (ILC2s) are innate counterparts to Th2 cells and key early responders in helminth infection. ILC2s have two subpopulations: tissue-resident “natural” nILC2s, present in the lungs at homeostasis, and “inflammatory” iILC2s, which appear transiently in the lungs during the response to helminth infection. We aim to determine the fate of pulmonary iILC2s and hypothesize that pulmonary iILC2s acquire an nILC2-like phenotype and make biologically relevant long-term contributions to the tissue-resident ILC2 pool. Early studies demonstrated that iILC2s can convert to an nILC2 phenotype, but the prevailing view in the field is that the nILC2 population is maintained through self-renewal. However, fate-mapping models show an external contribution to the pulmonary ILC2 population which corresponds with an influx of iILC2s. We have further characterized the pulmonary ILC2 population during helminth infection and found an intermediate-phenotype population 8 days post infection. Preliminary flow cytometry and scRNA-seq data from congenic transfer experiments indicate that iILC2s may acquire an nILC2 phenotype in vivo. Preliminary multiple infection experiments indicate that mice lacking a pulmonary iILC2 response have smaller nILC2 compartments compared to wildtype counterparts after 3 infections. We are further testing our hypothesis using fate-mapping models and congenic transfer experiments in conjunction with single-cell sequencing approaches to more rigorously confirm these findings. Understanding the contribution of iILC2s to the long-term tissue-resident ILC2 population could lead to therapies in diseases with ILC2 involvement including helminth infection and steroid-resistant asthma. Supported by NIH grant R01 AI56901-0