ILC2s govern imprinting of alveolar macrophage-mediated immunity upon secondary helminth infection in the lung

Hookworm parasites migrate through the pulmonary system as part of their lifecycle, causing significant tissue damage that activates tissue-resident cell populations such as ILC2s. These cells drive type 2 immune responses critical for wound healing and the development of protective immunity. Macrophages, particularly monocyte-derived macrophages that seed the lung after infection, are central effectors of these responses and may be distinct from the tissue-resident populations they replace. However, the cellular and molecular factors governing the attrition of tissue-resident (TR) macrophages and their replacement remain poorly understood. We find that ILC2s and IL-4/IL-13-producing CD4 + T cells bi-directionally interact to regulate alveolar macrophage (AM) populations during infection. In the absence of these cells, type 2 immune responses are muted, leading to impaired anti-parasitic immunity in the lung during re-infection. This correlates with diminished expansion of type 2-polarized monocyte-derived alveolar macrophages (Mo-AMs), which are metabolically and transcriptionally distinct from TR-AMs. While Mo-AMs highly upregulated expression of Arg1, this was not essential for development of protective immunity in the lung. Concomitant with a more glycolytic metabolism, ILC2-induced Mo-AMs selectively upregulate arachidonate 15-lipoxygenase (Alox15), which promotes the capacity of macrophages to attack parasites in vitro. These results identify ILC2s as critical regulators of alveolar macrophage dynamics and important mediators of their function during helminth infection of the lung.