Group 2 Innate Lymphoid Cells Must Partner with the Myeloid-Macrophage Lineage for Long-Term Postviral Lung Disease

Kangyun Wu, Xinyu Wang, Shamus P. Keeler, Benjamin J. Gerovac, Eugene V. Agapov, Derek E. Byers, Susan Gilfillan, Marco Colonna, Yong Zhang, Michael J. Holtzman

Research output: Contribution to journalComment/debate

Abstract

Group 2 innate lymphoid cells (ILC2s) are implicated in host defense and inflammatory disease, but these potential functional roles need more precise definition, particularly using advanced technologies to better target ILC2s and engaging experimental models that better manifest both acute infection and chronic, even lifelong, disease. In this study, we use a mouse model that applies an improved genetic definition of ILC2s via IL-7r-conditional Rora gene targeting and takes advantage of a distinct progression from acute illness to chronic disease, based on a persistent type 2 immune response to respiratory infection with a natural pathogen (Sendai virus). We first show that ILC2s are activated but are not required to handle acute illness after respiratory viral infection. In contrast, we find that this type of infection also activates ILC2s chronically for IL-13 production and consequent asthma-like disease traits that peak and last long after active viral infection is cleared. However, to manifest this type of disease, the Csf1-dependent myeloid-macrophage lineage is also active at two levels: first, at a downstream level, this lineage provides lung tissue macrophages (interstitial macrophages and tissue monocytes) that represent a major site of Il13 gene expression in the diseased lung; and second, at an upstream level, this same lineage is required for Il33 gene induction that is necessary to activate ILC2s for participation in disease at all, including IL-13 production. Together, these findings provide a revised scheme for understanding and controlling the innate immune response leading to long-term postviral lung diseases with features of asthma and related progressive conditions.

Original languageEnglish
Pages (from-to)1084-1101
Number of pages18
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume205
Issue number4
DOIs
StatePublished - Aug 15 2020

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